Osteogenesis imperfecta

Chapter 61

Osteogenesis imperfecta David W. Rowe Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, United States

Chapter outline Introduction 1489 Clinical classification 1490 Severe-deforming osteogenesis imperfecta 1490 Mild nondeforming osteogenesis imperfecta 1491 Molecular classification 1491 Primary mutations within type I collagen genes A1 and A2 1491 Mutation of genes that modify the synthesis of type I collagen chains 1492 Mutations that control the level of differentiation of osteoblasts 1492 Mutation of genes that regulate the maturation of secreted procollagen into collagen fibril 1492 Pathophysiology of osteogenesis imperfecta 1493

Osteogenesis imperfecta secondary to production of an abnormal collagen molecule Osteogenesis imperfecta due to underproduction of a normal type I collagen molecule Therapeutic options Antiresorptive agents Anti-TGFß and anti-activin agents Anabolic agents Cell and gene-therapy options Use of induced pluripotential stem cells as a diagnostic tool References Further reading

1493 1495 1496 1496 1496 1496 1497 1497 1498 1505

Introduction There has been a remarkable expansion in the complexity of the genetic mechanisms that result in a clinical diagnosis of osteogenesis imperfecta (OI). This genetic disorder continues to be the paradigm for understanding the molecular basis of heritable connective tissues and evaluating therapeutic strategies for disorders affecting the mineralized skeleton. Some advances are a consequence of the new DNA sequencing technologies, transgenic animal models, and precise clinical observation, while others reflect the concerted efforts of parent supports and collaborating clinical centers to develop multicenter observational studies and clinical trials. This chapter will attempt to convey why this is an exciting time for physicians and scientists, who are beginning to see significant progress in appreciating the complexities of the disease and developing treatments tailored for the specific individual. While it is still useful to characterize the clinical severity of OI as nondeforming, progressively deforming, and perinatal lethal, this does not help in appreciating the diverse genetic causes of the bone disease, and it probably oversimplifies the clinical spectrum of any specific mutation. Specifically, the heterogeneity of clinical severity is remarkable for a similar type of mutation, even with the same mutation within the same family. This variability is evident in recent reviews of the genetic subtypes of OI, in which almost all are described as variable or mild to severe. The basis for this clinical appearance is termed phenotypic variance and ascribed to both environmental factors and genetic loci that can interact with dominantly inherited mutations. A recent example is demonstrated in a Wnt1 mutation in a three-generational family with different disease severity that was attributable to a small gene duplication unrelated to the location of Wnt1 (Alhamdi et al., 2018). Similar intrafamilial variability has been observed in other genetic forms of OI (Pollitt et al., 2016; Rauch et al., 2013; Galicka et al., 2005). A more detail discussion for the basis of genetic variation affecting phenotype is found in the genetic literature (Pai et al., 2015; Burrows et al., 2016), and its implications for OI will be discussed in the last section of this chapter.

Principles of Bone Biology. https://doi.org/10.1016/B978-0-12-814841-9.00061-0 Copyright © 2020 Elsevier Inc. All rights reserved.

1489

1490 PART | II Molecular mechanisms of metabolic bone disease

The major contribution to assessing the disease severity and natural history of OI has come from the interinstitutional collaborations that arose from the leadership of patient-support groups including the Osteogenesis Imperfecta Foundation (OIF, 2019), Children’s Brittle Bone Foundation (CBBF, 2019), and the National Organization for Rare Disorders (NORD, 2019). The initial consortium, called the Linked Clinical Research Centers, demonstrated its ability to capture and analyze clinical data from 544 OI subjects. This accomplishment led to the formation of the Brittle Bone Disorders Consortium (BBDC) (BBDC, 2019) as a recognized part of the NIH-funded Rare Diseases Clinical Research Network (RDCRN, 2019). From these efforts, more comprehensive descriptions of disease severity, nonskeletal effects, and treatment outcomes are being to appear.

Clinical classification Severe-deforming osteogenesis imperfecta With the prenatal identification of OI using 3-D ultrasound and CT imaging (Ulla et al., 2011; Akizawa et al., 2012; Suzumori et al., 2011), infants that in the past would not have survived a vaginal delivery are now among those individuals with the most severe forms of skeletal deformity. The cranium is unusually soft and molded and may be fractured at birth. Intracranial bleeding may have occurred. The sclerae are deep blue. The limbs are deformed and short, raising the consideration of hypophosphatasia, achondrogenesis, and thanatophoric dwarfism in the diagnosis. Multiple fractures are seen on X-ray, and the extremities appear broad and crumpled. The critical problem is neonatal pulmonary insufficiency that may lead to death in the first postnatal week (Shapiro et al., 1989). Faulty thoracic musculoskeletal development also limits respiratory function in the majority of cases (LoMauro et al., 2018). Retrospective studies prior to (Shapiro, 1985) and after instituting advanced neonatal care (Folkestad, 2018) still find a higher rate of death in the first year of life than for a reference population, which persists through early childhood. The impact of drug intervention on these early disease processes is yet to be determined (Palomo et al., 2015). Infants born with fractures and deformity who survive the perinatal period continue to experience multiple fractures with deformities and significant molding of the calvarium (Sinikumpu et al., 2015). Fractures may continue to occur during early childhood that may preclude a normal pattern of ambulation and require the assistance of a walker or wheelchair. Surgical intervention with limb straightening using expandable rods appears to improve ambulation (Franzone et al., 2017; Grossman et al., 2018; Ashby et al., 2018; Gardner et al., 2018), particularly when used in combination with antiresorptive therapy (Ruck et al., 2011, Anam, 2015). Deformity of the thoracic cage (pectus carinatum, pectus excavatum) may be present in early childhood and advance as scoliosis and vertebral compression increase (LoMauro et al., 2018). Vertebral compression, most commonly of the central or “codfish” type, begins shortly after birth and progresses relentlessly prior to puberty (Engelbert et al., 2003; Wallace et al., 2017). Although antiresorptive drugs increase vertebral bone density, they do not affect the progression of kyphoscoliosis. Surgical correction becomes necessary when lung mechanics are compromised (Liu et al., 2017; Piantoni et al., 2017; O’Donnell et al., 2017). Fortunately, the complication associated with the anesthesia needed for these orthopedic procedures is well appreciated and rarely experienced (Bojanic et al., 2011; Rothschild et al., 2018). Young adults who reach skeletal maturity, many of whom have been treated with antiresorptives, still have short stature, usually in proportion to the severity of their skeletal deformities (Palomo et al., 2015; Germain-Lee et al., 2016; Jain et al., 2019). Dental abnormalities including malocclusion (Nguyen et al., 2017; Jabbour et al., 2018), tooth agenesis (Malmgren et al., 2017), and tooth degeneration requiring dental interventions (Thuesen et al., 2018), resulting in a low oral health-related quality of life (Najirad et al., 2018). Despite dental issues and enduring bone pain with or without an associated fracture (Zack et al., 2005; Folkestad et al., 2017; Tsimicalis et al., 2018), overall quality of life is remarkably positive (Dahan-Oliel et al., 2016; Hald et al., 2017; Tsimicalis et al., 2018; Bendixen et al., 2018). Developing better tools for assessing quality of life issues not currently appreciated by the medical community is a major focus of the BBDC (Swezey et al., 2019). Issues that develop with increasing age for individuals with OI include cardiovascular, pulmonary, and neurological difficulties, which probably account for the modestly reduced life span of adults with the severer forms of OI (Folkestad, 2018). Beginning in childhood, evidence can be demonstrated of aortic root enlargement (Al-Senaidi et al., 2015; Rush et al., 2017) that can lead to valvular insufficiency (Migliaccio et al., 2009; Radunovic et al., 2011; Ashournia et al., 2015), heart failure (Radunovic et al., 2015; Folkestad et al., 2016), and reports of aortic dissection (Balasubramanian et al., 2019). In addition to structural deformities of the chest wall that compromise pulmonary function, primary pathology within the lung tissue, and skeletal muscle weakness, may also contribute to respiratory symptoms (Arponen et al., 2018; Tam et al., 2018). Because of molding of the base of the skull, subjects with severely compromised bone strength are at risk for developing basilar invagination (Janus et al., 2003; Khandanpour et al., 2012; Cobanoglu et al., 2018) that may

Osteogenesis imperfecta Chapter | 61

1491

cause brain stem compression with both respiratory and neurological complications and sudden death (Janus et al., 2003; Kovero et al., 2006). Charnas reported communicating hydrocephalus in 17 out of 76 subjects with OI (Charnas et al., 1993). Brain stem compression requiring surgical decompression or reinforcement of the craniocervical junction is extremely complex, requiring mechanical support, transoral clivectomy, and decompression of the posterior fossa where respiratory center function is compromised (Cobanoglu et al., 2018).

Mild nondeforming osteogenesis imperfecta Individuals who sustain an increased number of fractures that heal without deforming are considered to have type I OI. Despite their apparent normalcy, they are susceptible to complications that affect quality of life, particularly scoliosis and vertebral compression fractures (Ben Amor et al., 2013). A recent survey of 117 affected individuals demonstrated a smaller birth size, impaired adolescent growth spurt, and eventually lower height (Graff et al., 2017). Even during childhood and early adolescence, reduced measurements of gait strength, possibly reflecting muscle weakness (Veilleux et al., 2014; Pouliot-Laforte et al., 2015; Pavone et al., 2017) or ligamentous laxity, are evident by formal gait analysis (Garman et al., 2017). Because patients with type I OI do not benefit from antiresorptive drugs, there was little to offer this large segment of individuals with OI. However, recent studies show the promise of a significant response to anabolic agents such as PTH (Gatti et al., 2013; Orwoll et al., 2014; Leali et al., 2017) and antisclerostin (Glorieux et al., 2017; Nicol et al., 2018) that, if utilized as the skeleton is forming, might mitigate many of these complications.

Molecular classification The previous edition of the chapter listed nine OI types, two of which were based on clinical phenotyping. In the past 2 years there have been five comprehensive review articles (Forlino et al., 2016; Kang et al., 2017; Lim et al., 2017; Marini et al., 2017; Morello, 2018) listing 18 recognized types and another 2 with OI features and a known genetic mechanism that have not joined the typing list. These review articles provide clear distinctions of the broad range of mutations that interfere with the formation of a stable type I collagen extracellular matrix, the major component of bone, skin, and tendons/ligaments. Rather than repeat the important contributions of these reviews, highlights of each type of molecular mechanism will be presented.

Primary mutations within type I collagen genes A1 and A2 By far, these mutations are the most common genetic cause of OI (Rauch et al., 2010; Zhang et al., 2012), but the location of the mutation has a large impact on clinical severity. The more severe forms (types II, III, and IV) usually result from a mutation in either gene that interferes with the formation of a stable collagen helix and its ability to interact with noncollagenous protein within the bone matrix (Marini et al., 2007). The mutations can be a single base change (usually glycine substitution) or the deletion of an internal segment of the gene. Efforts to associate disease severity with mutation location have been published (Marini et al., 2007; Bodian et al., 2009), but its utility as a predictor of individual skeletal health has not reached clinical fruition, in part due to variations in genetic background and the increasing use of drug interventions. Because these are dominant mutations, pedigrees with multiple affected individuals across generations are the rule. However, the occurrence of OI in a family without a prior history, particularly if more than one child is affected, raises the possibility of germinal mosaicism in one of the parents (Pyott et al., 2011). Thus, knowing the underlying mutation in the affected child is essential in genetic testing of the parents to distinguish germinal mosaicism from a recessive form of OI (see below). Qualified academic and commercial sites for obtaining mutation discovery are maintained on the Osteogenesis Imperfecta Foundation website (OIF-Testing, 2019). Type I OI is clinically and molecularly distinct from types II, III, and IV. The molecular hallmark is half-normal production of a normal type I collagen molecule and an apparently normal extracellular matrix. The mutation is usually due to either single base change in the collagen type I, alpha 1 (Col1A1) gene that generates a premature stop codon or a splice site mutation that deletes an exon and places the downstream exons out of frame, bringing a stop codon in-frame. In either case, the affected Col1A1 transcript is destroyed by a cellular mechanism called nonsense-mediated decay (Lykke-Andersen et al., 2015). Although this haploid-insufficient mutation is inherited as dominant (Ben Amor et al., 2013), the phenotypic variation may omit family members that only present in later life with osteoporosis. This is another example of why knowing the mutation of affected family members is useful for detecting those who would be predisposed to early-onset osteoporosis (Arundel et al., 2015; Makitie et al., 2017) and might benefit from therapy to delay that outcome (see later).

1492 PART | II Molecular mechanisms of metabolic bone disease

Mutation of genes that modify the synthesis of type I collagen chains The majority of these mutations are recessively inherited because they affect enzymes or other processing proteins that provide sufficient activity in the heterozygous state. These disorders usually appear as new disorders within families without previous skeletal abnormalities and point to the importance of mutation identification for predicting natural history and recurrence risk. A number of genes that encode the enzyme complexes that hydroxylate proline at the 3-OH (OI types VII-CRTAP, VIII-P3H1, and IX-PPIB; Barbirato et al., 2015) and 4OH positions (ColeeCarpenter syndrome, P4H1; Balasubramanian et al., 2018; Rauch et al., 2015), and lysine within the helical or telopeptide (Bruck syndrome, PLOD2; Lv et al., 2018; Leal et al., 2018), have been identified and have clinical features of the more severe forms of OI. The hydroxylation steps occur within the Golgi system and are dependent on proper folding and transit through the system by specific chaperones (OI type X, SERPINH1d Song et al., 2018; Marshall et al., 2016 and OI type XI, FKBP10dKelley et al., 2011). These mutations either slow transit of the assembly of normal collagen molecules through the rough ER or fail to detect and remove misfolded collagen molecules. The importance of the TMEM38B gene that encodes an ER calcium transport protein necessary for efficient processing and secretion of collagen was revealed by studying another rare recessive OI phenotype classified as OI type XIV (Volodarsky et al., 2013; Webb et al., 2017).

Mutations that control the level of differentiation of osteoblasts The osteogenic lineage is first recognized as a migratory myofibroblast that enters the nonproliferative stage of enhanced production of extracellular matrix proteins and ends as an embedded osteocyte. Mutations of type I collagen disrupt this sequence of events, which can be recognized in primary cell culture by the low expression of genes that reflect full osteogenic differentiation. Thus, it would not be surprising that other genes controlling differentiation may result in an OI phenotype, although in these cases severity may be less because the extracellular matrix is not abnormal. The first example was the discovery of a heterozygous null mutation of Sp7/Osterix (OI type XIII; Lapunzina et al., 2010; Fiscaletti et al., 2018), a transcription factor required for progenitor cells to enter into and maintain osteogenic differentiation. Subsequently, homozygous null mutations of the Wnt 1 gene (OI type XV), which maintains the differentiated state of the osteoblast, were demonstrated to cause severe OI, while the heterozygous state presented as premature osteoporosis (Palomo et al., 2014; Panigrahi et al., 2018). Additional mutations resulting in OI have directed attention to more complex and previously unappreciated mechanisms that impact the extent or tempo of osteogenic differentiation. OI type V is dominantly inherited and has the distinctive phenotype features of interosseous membrane calcification, hyperplastic callus formation at sites of bone fracture, and severe bimaxillary malocclusion in addition to bone fragility (Cheung et al. 2007, 2008; Retrouvey et al., 2018). The phenotype is linked to the IFITM5 gene, which encodes the BRIL protein strongly expressed in osteoblasts. The IFITM5 mutation either adds an additional five amino acids to the N-terminal of the protein or a point mutation in the body of the gene (Shapiro et al., 2013; Rauch et al., 2013; Fitzgerald et al., 2013; Brizola et al., 2015). In either case, enhanced osteogenic differentiation and excessive mineralization of the extracellular matrix in cultured cells and mouse models appears to be a consequence of this gene mutation (Rauch et al., 2018; Blouin et al., 2017). In contrast, OI type VI is recessively inherited and has the unusual history of mild to no skeletal abnormalities at birth followed by development of typical bone fractures with deformity during childhood. Histological analysis of bones revealed distorted and impaired matrix mineralization (Trejo et al., 2017). Null mutations in the SERPINf1 gene have been identified for this phenotype (Wang et al., 2017; Homan et al., 2011). This gene produces the well-characterized pigment epithelium-derived factor (PEDF) studied in other clinical settings for its antithrombotic and antivascular properties (Yamagishi et al., 2010; Michalczyk et al., 2018; Eslani et al., 2017). When a mouse model was created, a defect in osteoblast differentiation to a mature osteocyte was demonstrated. Currently, mechanisms dependent on PEDF interaction with Wnt signaling pathways that control differentiation and mineralization are being studied. Because PEDF is a circulating protein (Rauch et al., 2012), efforts to provide this factor using genetic tools are being explored in mouse models with equivocal results to date (AlJallad et al., 2015; Belinsky et al., 2016).

Mutation of genes that regulate the maturation of secreted procollagen into collagen fibril Extracellular processing procollagen is required for helical domains to self-align into growing collagen fibril prior to interaction with the other noncollagenous proteins that embed the growth factors necessary for the regenerative properties of bone. The first example is loss of function of the BMP1 gene resulting in type XII OI (Xu et al., 2019; Pollitt et al., 2016;

Osteogenesis imperfecta Chapter | 61

1493

Cho et al., 2015). The encoded protein is a metalloproteinase that not only cleaves the C-terminal propeptide of types I and III collagen but also is a protease for other proteins including prodecorin (Syx et al., 2015), lysyl oxidase, latent TGF-b1, BMP-2/4, GDF-8/11, and IGFs as well as the release of antiangiogenic fragments from parent proteins, all of which promote bone healing (Muir et al. 2014, 2016; Asharani et al., 2012; Jasuja et al., 2007; Ge et al., 2006). Another example of a collagen-interacting protein was found in homozygous base substitutions of the SPARC gene (OI type IV; MendozaLondono et al., 2015). Osteonectin is the encoded protein widely expressed in many connective tissues and in bone appears to influence both osteogenic differentiation and collagen cross-linking (Rosset et al., 2016).

Pathophysiology of osteogenesis imperfecta The fundamental abnormality in OI is an inability to produce a bone matrix capable of providing the mechanical, remodeling, and regenerative properties of the axial, appendicular, and cranial skeleton. While most attention is focused on bone and dentin, other type I collagenerich mineralizing tissues such as the enthesis, periodontal ligaments, and a fibrocartilaginous joint (the temporomandibular joint) are also likely to be affected. Two fundamental differences in the pathophysiologic mechanisms of OI influence how to conceptualize the disease process and eventually shape a therapeutic response. Type I OI and to a lesser extent types XIII (Sp7) and XV (Wnt) produce a normal collagen molecule, although of insufficient quantity to meet load requirements. In contrast, types IIeXI produce an abnormal collagen molecule that has adverse effects on osteoblasts and the function of the extracellular matrix. Even though disease severity may merge between the clinical types, it is important to distinguish the cellular and regulatory differences of low production versus an abnormal collagen molecule.

Osteogenesis imperfecta secondary to production of an abnormal collagen molecule Whether due to a primary mutation with the type I collagen gene or in genes that modify the formation of the triple helical molecule, the resulting consequences act at cellular and physiological levels (Fig. 61.1). The impaired processing of the mutant collagen through the rough ER adversely impedes the progression to full differentiation of the osteogenic lineage, possibly due to activation of ER stress responses (Scheiber et al., 2019; Mirigian et al., 2016; Lindert et al., 2015; Bateman et al., 2019). In vitro this effect can be observed as failure to achieve gene markers of full osteogenic differentiation (Fedarko et al., 1995; Kalajzic et al., 2002; Gioia et al., 2012), while in vivo there is an imbalance in the RANKL/OPG ratio indicative of a preponderance of early osteogenic linage cells (Li et al., 2010). During childhood when the need for matrix apposition and bone remodeling is the greatest, this primary abnormality of lineage progression is compounded by deposition of a defective bone matrix that sustains microfractures. Osteocytes, in response to changes in perceived load, may initiate additional sites of bone resorption/remodeling by the release of RANKL (Zimmerman et al., 2018). The combined result is high osteoclastic activity and a high bone turnover rate that cannot be compensated for by the osteoblast lineage. Clinically this high turnover state is assessed by the type I collagen cross-linking peptides (CTXs) and histologically by markers of high bone formation and bone erosion (Rauch et al., 2006). Intervention with inhibitors of osteoclast formation, either a bisphosphonate or anti-RANKL antibody, is effective in interrupting high turnover state and providing the osteogenic cells to enhance overall matrix accumulation (Palomo et al., 2015). Bone apposition does increase in spite of a suppression of osteogenic markers in growing children. However, once full somatic growth is achieved, the effect of osteoclastic suppression diminishes because bone remodeling is impacted, and the consequences of continued treatment can become evident (Nicolaou et al., 2012; Hegazy et al., 2016; Trejo et al., 2017; Andersen et al., 2019). Anabolic therapies have generally been ineffective during the period of rapid growth, in part because the osteogenic lineage is fully taxed at this time. However, mouse model studies suggest these agents may play roles in enhancing matrix formation during somatic growth when used sequentially with an antiresorptive agent (Olvera et al., 2018). Another approach for stimulating bone anabolism is based on the known weakness of skeletal muscle in OI and the loading effect muscle has on maintaining bone mass. Because the myostatin D knockout mouse has a high skeletal muscle mass (McPherron et al., 1997), drug inhibition of this muscle mass regulator has been shown to increase bone mass in experimental mouse models (Lee et al., 2016). This logic appears to apply to OI also, as two different research groups have shown increases in bone and muscle mass in a mouse model of severe OI (DiGirolamo et al., 2015; Oestreich et al., 2016). Left unexplained are the nonosseous features of the more severe forms of OI, which include pulmonary fibrosis and aortic root dilatation. These are features of Marfan’s disease that have previously been associated with a chronic TGFb-induced inflammatory state. A seminal paper reported that a similarly high TGFb state exists in murine models of OI and that treatment with anti-TGFß antibodies both increased bone mass and reduced pulmonary inflammation (Grafe

1494 PART | II Molecular mechanisms of metabolic bone disease

FIGURE 61.1 Pathophysiological dynamics in OI. (A) Normal physiological regulation. Osteoblasts have an exceptionally high production rate of extracellular matrix molecules including type I collagen. The secreted fibrils align into collagen fibrils, bind other matrix molecules and sequester a variety of local acting bone growth factors including TGFs, BMPs and IGFs. During somatic growth (1), systemic hormones drive osteoblasts to meet the need of the elongating bones and increasing body weight. This net accumulation of bone matrix is termed bone modeling. Additional loading forces, probably acting through osteocytes (2a), initiate the bone remodeling process in which osteoclasts resorb bone matrix and release bone growth factors (2b) that in turn activate the osteogenic lineage to proliferate and replace the resorbed bone matrix (2c). (B) Pathophysiological regulation of OI. The inherent inability of the osteogenic lineage to produce mature osteoblasts and the inefficient production/secretion of type I collagen in those cells that do achieve full differentiation reduce the amount of matrix that can be produced in a growing bone. Furthermore, the matrix formed is not normally aligned and probably does not properly bind matrix proteins and growth factors (1). Thus, during the bone modeling phase of skeletal growth, both the mechanical and regulatory function of the growing bone is compromised. (a) mechanical: The innumerable asymptomatic microfractures activate the osteocyte remodeling process (2a). Because the intensity of the osteoclastic activity (2b) drives the recruitment of the osteoblastic lineage (2c), the process is termed a high bone turnover state, but in this case the matrix produced is no better than what was removed. The unabated high remodeling state is associated with an extremely low bone mass, multiple fractures, bone pain and bone deformity. Thus, suppression of the osteoclast function breaks this cycle and allows for bone matrix accumulation particularly during somatic growth. (b) regulatory: Because the disordered matrix does not retain embedded growth factors adequately, the high turnover state releases more factors than usual (3a). The inflammatory growth factors (Fig. 61.2) can act locally by augmenting the myeloid precursor balance of macrophages to osteoclasts, while impeding the expansion of the osteoblast lineage. When these growth factors escape to the peripheral circulation, they can induce an inflammatory state in peripheral tissues. Thus, suppression of high bone turnover in children can lead to bone accumulation and possibly less peripheral inflammatory activity. However, in adults in which a moderately elevated rate of bone turnover is not a basis for osteoclast suppression, the released growth factors could lead to inflammatory tissue damage in OI target tissues. Such a mechanism argues for the use of pharamcologics that suppress the action of the released inflammatory growth factors.

et al., 2014). This systemic inflammatory state is also evident in hematopoietic tissues in mice (Matthews et al., 2017) and human subjects (Brunetti et al., 2016). What is the cause of this increase in circulating TGFb? The mechanism in Marfan’s disease is mutations in the fibrillin-1 gene that inactivate the ability of this protein to maintain TGBFb in a latent inactive form (Ramirez et al., 2018). Perhaps the same mechanism exists in bone. Numerous growth factors including TGFb, BMPs, and IGFs are contained with the bone matrix, and the loss of their regulated release, particularly in a high turnover state, may be another consequence of the disrupted bone matrix. Support for this circular mechanism for high bone resorption is the direct effect that TGFb has on stimulating the macrophage-to-osteoclast lineage (Yasui et al., 2011; Omata et al., 2016) and the observation that anti-TGFß treated OI mice increased their bone mass by a suppression of osteoclast number and reduction in bone formation markers (Grafe et al., 2014). Furthermore, the increased bone mass observed in anti-myostatin D-treated mice resulted from the same combination of reduced osteoclast number and reduced markers of bone formation (DiGirolamo et al., 2015; Oestreich et al., 2016). Myostatin has additional effects on tissues other than muscle including promoting osteoclast differentiation (Dankbar et al., 2015), so the muscle-loading effect on bone may in part be attributable to suppression of the cell inflammatory process. The similarity of effect of anti-TGBß and antimyostatin/activin 2A receptor decoy therapy becomes clearer when the confluence of pathways that influence the SMAD 2/3 pathway in different types is examined (Fig. 61.2). Thus, blocking activation of this pathway using antibodies to ligands or solubilized receptor peptides may be an additional therapeutic strategy that can be tailored to specific forms of OI or stages of its natural history.

Osteogenesis imperfecta Chapter | 61

1495

FIGURE 61.2 Inflammatory growth factors. Both activins/myostatin and TGFs can have an equivalent influence on the SMAD 2/3 pathway to activate the macrophage-driven inflammatory state as well as having primary effects on certain target tissues. The ligands bind to separate type 2 receptors (ACVR2A/B and TGBbR2) that in turn bind to different type I receptors (blue [gray in print version]) to activate the same SMAD pathway. The pathways can be interrupted either with antibodies to the ligands or soluble type 2 receptors that bind and inactivate the ligands.

Where these considerations may become important is with the use of therapeutics that suppress resorption or stimulate formation. Currently, CTXs are used to assess osteoclastic activity, but the use of additional blood studies that assess mediators or markers of chronic inflammation, as well as measures of bone matrix protein activity, may provide a better window into the balance of bone-intrinsic versus bone growth factor derived drivers of bone turnover (Nicol et al., 2019). Thus, states associated with bone modeling may facilitate a matrix that stabilizes the release of the bone-derived growth factors while high bone turnover in individuals who have achieved full somatic growth may favor the release of these factors. At this point it is unknown whether the suppression of osteoclastogenesis will have the effect of reducing the nonosseous complications of OI either directly, as with bisphonphonates and anti-RANKL drugs, or more systemically with drugs that act through activineSmad2/3 pathways. Conversely, drugs that stimulate new bone formation may have different effects on nonosseous tissues depending on the balance of modeling versus remodeling achieved by their administration.

Osteogenesis imperfecta due to underproduction of a normal type I collagen molecule The only mouse model of type I OI utilized a now disbanded genetic technique that shortened the life span of the line due to leukemia (Jacobsen et al., 2016; Jepsen et al., 1997). Thus, lacking a model that replicates this form of OI has hindered fully appreciating the pathogenesis and natural history effect of chronic underproduction of type I collagen. What is known from human fibroblast studies is that unlike the normal setting of twofold greater collagen chain production of a1(I) versus a2(I), equal production of a1(I) and a2(I) proteins results in the formation of a normal collagen heterotrimer, (a1(I)2 a2(I)1) (Rowe et al., 1985), while trimeric molecules composed of a1(I)1 a2(I)2 or a2(I)3 are unstable and degraded (Gauba et al., 2008; Kuznetsova et al., 2003). At this point, it is unclear whether this degradation process contributes to ER stress similar to that observed for cells exposed to a mutant collagen gene product. An additional complication for understanding the cellular environment are splice site mutations of the Col1A1 gene in which the resulting in-frame stop that normally would inactivate the transcript is alternatively skipped to create an in-frame deletion and a mutant Col1A1 chain (Bateman et al., 1999). Because the toxic effect of an abnormal collagen chain is strong, just a small proportion this product relative to total type I collagen produced in a type I OI mutation would contribute to a more severe clinical phenotype. Distinguishing the impact of low type I collagen accumulation alone versus a low product containing a small proportion of mutant molecules will be a challenge. Inactivation mutations of the collagen type I, alpha 2 (Col1A2) gene would be expected to produce a heterotrimer of three alpha chains (a1(I)3) that lacks the stability of the heterotrimer and would be expected to cause a bone phenotype (Kuznetsova et al., 2003). A spontaneous mutation in the Col1A2 gene in mouse that precludes formation of a heterotrimer is one of the major murine models for studying OI pathogenesis and various therapeutic interventions. Human subjects with a similar mutation have a severe phenotype in proportion to the extent that heterotrimer formation is impeded (Pace et al., 2008). However, a human subject with an inactivating mutation of the Col1A2 gene has been identified who presented as EhlerseDanlos and not OI (Schwarze et al., 2004). Reconciling these differences using murine models is likely to provide additional insights into cell and matrix factors that influence skeletal health. Even less understood is the consequence of a diminished content of type I collagenecontaining matrix in bone and other tissues relative the other matrix proteins that interact with this organizing molecule. Until shown otherwise, the underlying assumption is that increasing the type I collagen output should have a positive impact on skeletal health. The anabolic agents that enhance matrix production from osteoblasts and other type I collageneproducing cells needs to be explored, again using animal models prior to clinical trials. In contrast, OI-causing mutations that affect the progression of

1496 PART | II Molecular mechanisms of metabolic bone disease

osteogenic lineage will require a different therapeutic approach utilizing agents that enhance or block the pathways affected by the mutation. Many potential drug candidates are already available that will have to be personalized for the offending mutation. In all cases, including type I OI, initiating the intervention early in childhood when bone matrix is being accumulated will be important, and maintaining a lifestyle that is anabolic for the skeleton will have to be emphasized. In summary, the pathophysiological basis for OI is extremely heterogeneous and cannot be anticipated by clinical presentation alone. Clearly, molecular diagnosis will provide some insight into the likely cell and matrix consequences, and improved testing for bone metabolic and inflammatory markers will further refine the underlying factors determining disease severity and nonosseous outcomes.

Therapeutic options Although antiebone resorptive agents have changed the natural history of the more severe forms of OI, particularly in children, the specific drugs, how they are used, and their durations of treatment are not uniformly applied in the different treatment centers in the United States and elsewhere. Thus, for the individual physician who encounters an individual with OI, it is probably wise to refer to one of the major treatment centers so that the individual can be enrolled in one of a number of multicenter trials and benefit from the best clinical experience available (Montpetit et al., 2015). The centers provide the additional health-supporting advantages of physical and occupational therapies, contact with other affected families, and the resources of the Osteogenesis Imperfecta Foundation. Agents approved or under evaluation can be divided into three classes: antiresorptive, anti-Tgfß and antiactivin, and anabolic.

Antiresorptive agents Bisphosphonate in the form of short-acting pamidronate was the first agent successful in reducing fracture frequency in growing children. A major experience in using this drug was assembled by the Montreal treatment center (Glorieux et al., 1998; Arikoski et al., 2004) and was subsequently replicated at other centers (DiMeglio et al., 2004; Fleming et al., 2005). Most notable were a reduction in fractures, better formation vertebra, and improved linear growth. Because the drug requires intravenous administration that must be repeated 2e3 times each year, longer-acting forms such as zoledronate have received greater usage (Palomo et al., 2015; Tsimicalis et al., 2018). Oral forms such as alendronate and risedronate are also effective (Ward et al., 2011; Bishop et al., 2013) but have not become standard practice. The introduction of the anti-RANKL drug denosumab provided an entirely different approach for inhibiting bone resorption. Unlike bisphosphonates that induce osteoclast death after full differentiation has been achieved, denosumab prevents osteoclast differentiation. It has the advantage of infrequent injections and a predictable therapeutic window, and it has proven effective in early clinical trials (Hoyer-Kuhn et al., 2016). However, it has not become the primary treatment as of 2019.

Anti-TGFß and anti-activin agents Although there is strong data in mouse models of OI that these antibodies and soluble receptor peptides can be effective in suppressing osteoclastogenesis and potentially having other beneficial nonosseous effects (Grafe et al., 2014), a clinical trial is just being initiated through the BBDC.

Anabolic agents The use of bone anabolic agents to overcome the severe osteopenia of OI has always been an attractive approach and was the basis of growth hormone treatment in growing children. However, the experience in humans was inconclusive (Wright, 2000), and its use is no longer recommended. Use of PTH, teriparatide, has shown promise in adults, but its expense and a lack of coverage by most insurance companies has limited its use. The recent introduction of a PthrP analog, Abaloparatide, not only is as effective as PTH in increasing bone anabolism (Makino et al., 2018), but costs significantly less. Studies from osteoporotic patients that use PthrP and an antiresorptive sequentially are particularly encouraging (Le et al., 2019; Hiligsmann et al., 2019) and are leading to similar ongoing trials in adults with OI. Stimulating bone anabolism with antisclerostin antibodies shows significant positive effects in adults with OI. Markers of bone anabolism without an increase in bone turnover markers (Glorieux et al., 2017; Sridharan et al., 2018) suggest the modeling effect this drug is expected to deliver (Sinder et al., 2016; Sridharan et al., 2018). Although the initial application for osteoporosis was rejected by the FDA in 2017, this hurdle was cleared in 2019.

Osteogenesis imperfecta Chapter | 61

1497

Cell and gene-therapy options The high-profile announcements of stem cell and gene-correction possibilities for human disease have impacted potential treatment options for OI, particularly in young severely affected individuals. The rationale for either approach is the observation that parents with somatic mosaicism for a mutation that causes a severe form of OI in their child rarely have features of skeletal disfunction. The basis for this observation has not been directly tested, but it may reflect the superior competitive advantage that normal osteoblasts have for cell proliferation and matrix production relative to osteoblasts compromised by mutant collagen chains. It is possible that a degree of mosaicism sufficient to affect skeletal health could be achieved by either a cell-based or gene-therapy approach. Initial reports of bone marrow and bone marrow mesenchymal cell transplantation were performed without solid animal studies demonstrating that osteoblast engraftment by this means would have a significant impact on disease severity (Horwitz et al. 1999, 2002, 2008). Subsequent studies using more sensitive GFP reporter-based methods in mouse models have clearly demonstrated that systemic administration of stem cells capable of osteogenic differentiation does not engraft trabecular bone (Wang et al., 2005; Boban et al., 2010; Otsuru et al., 2017). Despite this basic animal work (Featherall et al., 2018), infusion of marrow-derived stromal cells is still being performed on an experimental basis (Le Blanc et al., 2005; Westgren et al., 2015; Gotherstrom et al., 2014) without clear-cut animal data to show that it is effective for engraftment (Millard et al., 2015). Direct introduction of mouse bone progenitor cells into the bone marrow cavity or an experimental defect space in mice leads to engraftment and integration with the host bone (Pauley et al., 2014; Gohil et al., 2016). In contrast, direct injection of whole bone marrow is not effective (Wang et al., 2005; Lee et al., 2019). Given the increasing success of drug interventions, this type of strategy would be limited as a supplement to orthopedic reconstructive procedures of the limb, vertebral, or basilar skull bones. However, this type of use will only be meaningful in the human clinical setting if the cells are isogenic with the individual subject. Claims that mesenchymal-derived cells are immune-privileged have not been validated for osteogenic engraftment (Bilic-Curcic et al., 2005). A possible solution to this problem is the use of patientderived induced pluripotential stem cells (iPSCs). By engineering a correction of the underlying OI mutation using CRISPR/Cas9 technology, it should be possible to generate otherwise normal patient-specific progenitor cells that would generate normal bone matrix in the region of their application. The molecular technologies to safely introduce a new gene into cells have improved to the point that they are now being applied in clinical trials for a number of hematopoietic disorders (Herrmann et al., 2018; Ahmed et al., 2018; Elsner et al., 2017). Animal studies are promising for other tissue types, particularly those that do not have a high level of cell turnover (Tabebordbar et al., 2016; Deverman et al., 2018). In the case of recessive forms of OI that result from a loss of enzymatic or chaperone function, gene replacement could be effective. The issue is the delivery method. While systemic administration is possible, the vast majority of osteogenic cells targeted would be mature cells that eventually would be replaced by nontargeted progenitors. However, it might be possible to transiently increase the progenitor cell number prior to administering the targeting vector to achieve a sufficient number of transformed cells to reach a mosaic threshold effect. While this might be an issue for children, bone-lining cells in adults may harbor the capacity for bone remodeling (Matic et al., 2016), making them an excellent target for genetic engineering. All of these potentially attractive approaches require small animal testing, which provides exquisitely sensitive and relatively low-cost test platforms to identify the most positive candidate vectors and application strategies. Once identified, they will need to be validated in principle in larger animal models prior to a stepwise clinical safety and efficacy trial.

Use of induced pluripotential stem cells as a diagnostic tool Given the increasing complexity of the various molecular forms of OI and the strong influence of background genes that further complicate disease pathogenesis, it is likely that animal models will never fully serve as models for specific individuals with OI. Because iPSCs express the genetic heterogeneity of their donor, they provide the opportunity for developing personalized therapeutic decisions (Kilpinen et al., 2017; DeBoever et al., 2017; Rowe et al., 2019). While obtaining primary osteoblastic cells from individual subjects is difficult, generation of iPSCs from peripheral blood provides the opportunity to direct these cells into the osteogenic lineage for detailed testing (Chen et al., 2013). Once a model for full osteogenic differentiation is achieved, protein and RNA expression studies can be initiated with best model in an in vivo setting for that specific subject (Xin et al., 2018). In this setting, not only can the effect of the mutation be assessed but also the identification of other genes whose products might interact with mutation becomes possible. To test the relative

1498 PART | II Molecular mechanisms of metabolic bone disease

impact of the candidate background gene to overall cellular phenotype, the CRISPR/Cas9 system can be used to revert the background gene to its wild-type form and determine whether this change improves the matrix production capability of the engineered osteoblasts (Xin, 2017, 2018). Knowing the contribution background gene may influence other combinatorial therapeutic options that are becoming available from osteoporosis/osteopenia research areas.

References Ahmed, S.G., Waddington, S.N., Boza-Moran, M.G., Yanez-Munoz, R.J., 2018. High-efficiency transduction of spinal cord motor neurons by intrauterine delivery of integration-deficient lentiviral vectors. J. Control. Release 273, 99e107. Akizawa, Y., Nishimura, G., Hasegawa, T., Takagi, M., Kawamichi, Y., Matsuda, Y., Matsui, H., Saito, K., 2012. Prenatal diagnosis of osteogenesis imperfecta type II by three-dimensional computed tomography: the current state of fetal computed tomography. Congenital. Anom. 52, 203e206. Al-Jallad, H., Palomo, T., Roughley, P., Glorieux, F.H., McKee, M.D., Moffatt, P., Rauch, F., 2015. The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI. Bone 76, 115e120. Al-Senaidi, K.S., Ullah, I., Javad, H., Al-Khabori, M., Al-Yaarubi, S., 2015. Echocardiographic evidence of early diastolic dysfunction in asymptomatic children with osteogenesis imperfecta. Sultan Qaboos Univ. Med. J. 15, e456ee462. Alhamdi, S., Lee, Y.C., Chowdhury, S., Byers, P.H., Gottschalk, M., Taft, R.J., Joeng, K.S., Lee, B.H., Bird, L.M., 2018. Heterozygous WNT1 variant causing a variable bone phenotype. Am. J. Med. Genet. 176, 2419e2424. Anam, E.A., Rauch, F., Glorieux, F.H., Fassier, F., Hamdy, R., 2015. Osteotomy healing in children With osteogenesis imperfecta receiving bisphosphonate treatment. J. Bone Miner Res 30, 1362e1368. Andersen, J.D., Bunger, M.H., Rahbek, O., Hald, J.D., Harslof, T., Langdahl, B.L., 2019. Do femoral fractures in adult patients with osteogenesis imperfecta imitate atypical femoral fractures? A case series. Osteoporos. Int. 30, 513e517. Arikoski, P., Silverwood, B., Tillmann, V., Bishop, N.J., 2004. Intravenous pamidronate treatment in children with moderate to severe osteogenesis imperfecta: assessment of indices of dual-energy X-ray absorptiometry and bone metabolic markers during the first year of therapy. Bone 34, 539e546. Arponen, H., Bachour, A., Back, L., Valta, H., Makitie, A., Waltimo-Siren, J., Makitie, O., 2018. Is sleep apnea underdiagnosed in adult patients with osteogenesis imperfecta? -a single-center cross-sectional study. Orphanet J. Rare Dis. 13, 231. Arundel, P., Bishop, N., 2015. Primary osteoporosis. Endocr. Dev. 28, 162e175. Asharani, P.V., Keupp, K., Semler, O., Wang, W., Li, Y., Thiele, H., Yigit, G., Pohl, E., Becker, J., Frommolt, P., Sonntag, C., Altmuller, J., Zimmermann, K., Greenspan, D.S., Akarsu, N.A., Netzer, C., Schonau, E., Wirth, R., Hammerschmidt, M., Nurnberg, P., Wollnik, B., Carney, T.J., 2012. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am. J. Hum. Genet. 90, 661e674. Ashby, E., Montpetit, K., Hamdy, R.C., Fassier, F., 2018. Functional outcome of humeral rodding in children with osteogenesis imperfecta. J. Pediatr. Orthop. 38, 49e53. Ashournia, H., Johansen, F.T., Folkestad, L., Diederichsen, A.C., Brixen, K., 2015. Heart disease in patients with osteogenesis imperfecta - a systematic review. Int. J. Cardiol. 196, 149e157. Balasubramanian, M., Padidela, R., Pollitt, R.C., Bishop, N.J., Mughal, M.Z., Offiah, A.C., Wagner, B.E., McCaughey, J., Stephens, D.J., 2018. P4HB recurrent missense mutation causing Cole-Carpenter syndrome. J. Med. Genet. 55, 158e165. Balasubramanian, M., Verschueren, A., Kleevens, S., Luyckx, I., Perik, M., Schirwani, S., Mortier, G., Morisaki, H., Rodrigus, I., Van Laer, L., Verstraeten, A., Loeys, B., 2019. Aortic aneurysm/dissection and osteogenesis imperfecta: four new families and review of the literature. Bone 121, 191e195. Barbirato, C., Trancozo, M., Almeida, M.G., Almeida, L.S., Santos, T.O., Duarte, J.C., Reboucas, M.R., Sipolatti, V., Nunes, V.R., Paula, F., 2015. Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta. Genet. Mol. Res. 14, 15848e15858. Bateman, J.F., Freddi, S., Lamande, S.R., Byers, P., Nasioulas, S., Douglas, J., Otway, R., Kohonen-Corish, M., Edkins, E., Forrest, S., 1999. Reliable and sensitive detection of premature termination mutations using a protein truncation test designed to overcome problems of nonsense-mediated mRNA instability. Hum. Mutat. 13, 311e317. Bateman, J.F., Sampurno, L., Maurizi, A., Lamande, S.R., Sims, N.A., Cheng, T.L., Schindeler, A., Little, D.G., 2019. Effect of rapamycin on bone mass and strength in the alpha2(I)-G610C mouse model of osteogenesis imperfecta. J. Cell Mol. Med. 23, 1735e1745. BBDC, 2019. Brittle Bone Disease Consortium. https://www.rarediseasesnetwork.org/cms/BBD. Belinsky, G.S., Sreekumar, B., Andrejecsk, J.W., Saltzman, W.M., Gong, J., Herzog, R.I., Lin, S., Horsley, V., Carpenter, T.O., Chung, C., 2016. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. FASEB J. 30, 2837e2848. Ben Amor, I.M., Roughley, P., Glorieux, F.H., Rauch, F., 2013. Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J. Bone Miner. Res. 28, 2001e2007. Bendixen, K.H., Gjorup, H., Baad-Hansen, L., Dahl Hald, J., Harslof, T., Schmidt, M.H., Langdahl, B.L., Haubek, D., 2018. Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study. BMC Oral Health 18, 35. Bilic-Curcic, I., Kalajzic, Z., Wang, L., Rowe, D.W., 2005. Origins of endothelial and osteogenic cells in the subcutaneous collagen gel implant. Bone 37, 678e687.

Osteogenesis imperfecta Chapter | 61

1499

Bishop, N., Adami, S., Ahmed, S.F., Anton, J., Arundel, P., Burren, C.P., Devogelaer, J.P., Hangartner, T., Hosszu, E., Lane, J.M., Lorenc, R., Makitie, O., Munns, C.F., Paredes, A., Pavlov, H., Plotkin, H., Raggio, C.L., Reyes, M.L., Schoenau, E., Semler, O., Sillence, D.O., Steiner, R.D., 2013. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1424e1432. Blouin, S., Fratzl-Zelman, N., Glorieux, F.H., Roschger, P., Klaushofer, K., Marini, J.C., Rauch, F., 2017. Hypermineralization and high osteocyte lacunar density in osteogenesis imperfecta type V bone indicate exuberant primary bone formation. J. Bone Miner. Res. 32, 1884e1892. Boban, I., Barisic-Dujmovic, T., Clark, S.H., 2010. Parabiosis model does not show presence of circulating osteoprogenitor cells. Genesis 48, 171e182. Bodian, D.L., Chan, T.F., Poon, A., Schwarze, U., Yang, K., Byers, P.H., Kwok, P.Y., Klein, T.E., 2009. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum. Mol. Genet. 18, 463e471. Bojanic, K., Kivela, J.E., Gurrieri, C., Deutsch, E., Flick, R., Sprung, J., Weingarten, T.N., 2011. Perioperative course and intraoperative temperatures in patients with osteogenesis imperfecta. Eur. J. Anaesthesiol. 28, 370e375. Brizola, E., Mattos, E.P., Ferrari, J., Freire, P.O., Germer, R., Llerena Jr., J.C., Felix, T.M., 2015. Clinical and molecular characterization of osteogenesis imperfecta type V. Mol. Syndromol. 6, 164e172. Brunetti, G., Papadia, F., Tummolo, A., Fischetto, R., Nicastro, F., Piacente, L., Ventura, A., Mori, G., Oranger, A., Gigante, I., Colucci, S., Ciccarelli, M., Grano, M., Cavallo, L., Delvecchio, M., Faienza, M.F., 2016. Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-alpha. Osteoporos. Int. 27, 2355e2365. Burrows, C.K., Banovich, N.E., Pavlovic, B.J., Patterson, K., Gallego Romero, I., Pritchard, J.K., Gilad, Y., 2016. Genetic variation, not cell type of origin, underlies the majority of identifiable regulatory differences in iPSCs. PLoS Genet. 12, e1005793. CBBF, 2019. Children’s Brittle Bone Foundation. https://globalgenes.org/support_organization/childrens-brittle-bone-foundation/. Charnas, L.R., Marini, J.C., 1993. Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta. Neurology 43, 2603e2608. Chen, I.P., Fukuda, K., Fusaki, N., Iida, A., Hasegawa, M., Lichtler, A., Reichenberger, E.J., 2013. Induced pluripotent stem cell reprogramming by integration-free Sendai virus vectors from peripheral blood of patients with craniometaphyseal dysplasia. Cell. Reprogr. 15, 503e513. Cheung, M.S., Azouz, E.M., Glorieux, F.H., Rauch, F., 2008. Hyperplastic callus formation in osteogenesis imperfecta type V: follow-up of three generations over ten years. Skeletal Radiol. 37, 465e467. Cheung, M.S., Glorieux, F.H., Rauch, F., 2007. Natural history of hyperplastic callus formation in osteogenesis imperfecta type V. J. Bone Miner. Res. 22, 1181e1186. Cho, S.Y., Asharani, P.V., Kim, O.H., Iida, A., Miyake, N., Matsumoto, N., Nishimura, G., Ki, C.S., Hong, G., Kim, S.J., Sohn, Y.B., Park, S.W., Lee, J., Kwun, Y., Carney, T.J., Huh, R., Ikegawa, S., Jin, D.K., 2015. Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta. Hum. Mutat. 36, 191e195. Cobanoglu, M., Bauer, J.M., Campbell, J.W., Shah, S.A., 2018. Basilar impression in osteogenesis imperfecta treated with staged halo traction and posterior decompression with short-segment fusion. J. Craniovertebral Junction Spine 9, 212e215. Dahan-Oliel, N., Oliel, S., Tsimicalis, A., Montpetit, K., Rauch, F., Dogba, M.J., 2016. Quality of life in osteogenesis imperfecta: a mixed-methods systematic review. Am. J. Med. Genet. 170A, 62e76. Dankbar, B., Fennen, M., Brunert, D., Hayer, S., Frank, S., Wehmeyer, C., Beckmann, D., Paruzel, P., Bertrand, J., Redlich, K., Koers-Wunrau, C., Stratis, A., Korb-Pap, A., Pap, T., 2015. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat. Med. 21, 1085e1090. DeBoever, C., Li, H., Jakubosky, D., Benaglio, P., Reyna, J., Olson, K.M., Huang, H., Biggs, W., Sandoval, E., D’Antonio, M., Jepsen, K., Matsui, H., Arias, A., Ren, B., Nariai, N., Smith, E.N., D’Antonio-Chronowska, A., Farley, E.K., Frazer, K.A., 2017. Large-scale profiling reveals the influence of genetic variation on gene expression in human induced pluripotent stem cells. Cell Stem Cell 20, 533e546 e7. Deverman, B.E., Ravina, B.M., Bankiewicz, K.S., Paul, S.M., Sah, D.W.Y., 2018. Gene therapy for neurological disorders: progress and prospects. Nat. Rev. Drug Discov. 17, 641e659. DiGirolamo, D.J., Singhal, V., Chang, X., Lee, S.J., Germain-Lee, E.L., 2015. Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta. Bone Res. 3, 14042. DiMeglio, L.A., Ford, L., McClintock, C., Peacock, M., 2004. Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta. Bone 35, 1038e1045. Elsner, C., Bohne, J., 2017. The retroviral vector family: something for everyone. Virus Gene. 53, 714e722. Engelbert, R.H., Uiterwaal, C.S., van der Hulst, A., Witjes, B., Helders, P.J., Pruijs, H.E., 2003. Scoliosis in children with osteogenesis imperfecta: influence of severity of disease and age of reaching motor milestones. Eur. Spine J. 12, 130e134. Eslani, M., Putra, I., Shen, X., Hamouie, J., Afsharkhamseh, N., Besharat, S., Rosenblatt, M.I., Dana, R., Hematti, P., Djalilian, A.R., 2017. Corneal mesenchymal stromal cells are directly antiangiogenic via PEDF and sFLT-1. Investig. Ophthalmol. Vis. Sci. 58, 5507e5517. Featherall, J., Robey, P.G., Rowe, D.W., 2018. Continuing challenges in advancing preclinical science in skeletal cell-based therapies and tissue regeneration. J. Bone Miner. Res. 33, 1721e1728. Fedarko, N.S., D’Avis, P., Frazier, C.R., Burrill, M.J., Fergusson, V., Tayback, M., Sponseller, P.D., Shapiro, J.R., 1995. Cell proliferation of human fibroblasts and osteoblasts in osteogenesis imperfecta: influence of age. J. Bone Miner. Res. 10, 1705e1712. Fiscaletti, M., Biggin, A., Bennetts, B., Wong, K., Briody, J., Pacey, V., Birman, C., Munns, C.F., 2018. Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone 110, 66e75. Fitzgerald, J., Holden, P., Wright, H., Wilmot, B., Hata, A., Steiner, R.D., Basel, D., 2013. Phenotypic variability in individuals with type V osteogenesis imperfecta with identical Ifitm5 mutations. J. Rare Disord. 1, 37e42.

1500 PART | II Molecular mechanisms of metabolic bone disease

Fleming, F., Woodhead, H.J., Briody, J.N., Hall, J., Cowell, C.T., Ault, J., Kozlowski, K., Sillence, D.O., 2005. Cyclic bisphosphonate therapy in osteogenesis imperfecta type V. J. Paediatr. Child Health 41, 147e151. Folkestad, L., 2018. Mortality and morbidity in patients with osteogenesis imperfecta in Denmark. Dan. Med. J. 65. Folkestad, L., Hald, J.D., Ersboll, A.K., Gram, J., Hermann, A.P., Langdahl, B., Abrahamsen, B., Brixen, K., 2017. Fracture rates and fracture sites in patients with osteogenesis imperfecta: a nationwide register-based cohort study. J. Bone Miner. Res. 32, 125e134. Folkestad, L., Hald, J.D., Gram, J., Langdahl, B.L., Hermann, A.P., Diederichsen, A.C., Abrahamsen, B., Brixen, K., 2016. Cardiovascular disease in patients with osteogenesis imperfecta - a nationwide, register-based cohort study. Int. J. Cardiol. 225, 250e257. Forlino, A., Marini, J.C., 2016. Osteogenesis imperfecta. Lancet 387, 1657e1671. Franzone, J.M., Bober, M.B., Rogers, K.J., McGreal, C.M., Kruse, R.W., 2017. Re-alignment and intramedullary rodding of the humerus and forearm in children with osteogenesis imperfecta: revision rate and effect on fracture rate. J. Child. Orthopaed. 11, 185e190. Galicka, A., Surazynski, A., Wolczynski, S., Palka, J., Popko, J., Gindzienski, A., 2005. Phenotype variability in a daughter and father with mild osteogenesis imperfecta correlated with collagen and prolidase levels in cultured skin fibroblasts. Ann. Clin. Biochem. 42, 80e84. Gardner, A., Sahota, J., Dong, H., Saraff, V., Hogler, W., Shaw, N.J., 2018. The use of magnetically controlled growing rods in paediatric Osteogenesis Imperfecta with early onset, progressive scoliosis. J. Surg. Case Rep. 2018, rjy043. Garman, C.R., Graf, A., Krzak, J., Caudill, A., Smith, P., Harris, G., 2017. Gait deviations in children with osteogenesis imperfecta type I. J. Pediatr. Orthop. https://doi.org/10.1016/B978-0-12-817454-8.00005-8. PMID 28777275. Gatti, D., Rossini, M., Viapiana, O., Povino, M.R., Liuzza, S., Fracassi, E., Idolazzi, L., Adami, S., 2013. Teriparatide treatment in adult patients with osteogenesis imperfecta type I. Calcif. Tissue Int. 93, 448e452. Gauba, V., Hartgerink, J.D., 2008. Synthetic collagen heterotrimers: structural mimics of wild-type and mutant collagen type I. J. Am. Chem. Soc. 130, 7509e7515. Ge, G., Greenspan, D.S., 2006. BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein. J. Cell Biol. 175, 111e120. Germain-Lee, E.L., Brennen, F.S., Stern, D., Kantipuly, A., Melvin, P., Terkowitz, M.S., Shapiro, J.R., 2016. Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care. Pediatr. Res. 79, 489e495. Gioia, R., Panaroni, C., Besio, R., Palladini, G., Merlini, G., Giansanti, V., Scovassi, I.A., Villani, S., Villa, I., Villa, A., Vezzoni, P., Tenni, R., Rossi, A., Marini, J.C., Forlino, A., 2012. ’Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta (OI), a new target for OI pharmacological therapy. Stem Cells 30, 1465e1476. Glorieux, F.H., Bishop, N.J., Plotkin, H., Chabot, G., Lanoue, G., Travers, R., 1998. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N. Engl. J. Med. 339, 947e952. Glorieux, F.H., Devogelaer, J.P., Durigova, M., Goemaere, S., Hemsley, S., Jakob, F., Junker, U., Ruckle, J., Seefried, L., Winkle, P.J., 2017. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J. Bone Miner. Res. 32, 1496e1504. Gohil, S.V., Kuo, C.L., Adams, D.J., Maye, P., Rowe, D.W., Nair, L.S., 2016. Evaluation of the donor cell contribution in rhBMP-2 mediated bone formation with chitosan thermogels using fluorescent protein reporter mice. J. Biomed. Mater. Res. A 104, 928e941. Gotherstrom, C., Westgren, M., Shaw, S.W., Astrom, E., Biswas, A., Byers, P.H., Mattar, C.N., Graham, G.E., Taslimi, J., Ewald, U., Fisk, N.M., Yeoh, A.E., Lin, J.L., Cheng, P.J., Choolani, M., Le Blanc, K., Chan, J.K., 2014. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl. Med. 3, 255e264. Grafe, I., Yang, T., Alexander, S., Homan, E.P., Lietman, C., Jiang, M.M., Bertin, T., Munivez, E., Chen, Y., Dawson, B., Ishikawa, Y., Weis, M.A., Sampath, T.K., Ambrose, C., Eyre, D., Bachinger, H.P., Lee, B., 2014. Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta. Nat. Med. 20, 670e675. Graff, K., Syczewska, M., 2017. Developmental charts for children with osteogenesis imperfecta, type I (body height, body weight and BMI). Eur. J. Pediatr. 176, 311e316. Grossman, L.S., Price, A.L., Rush, E.T., Goodwin, J.L., Wallace, M.J., Esposito, P.W., 2018. Initial experience with percutaneous IM rodding of the humeri in children with osteogenesis imperfecta. J. Pediatr. Orthop. 38, 484e489. Hald, J.D., Folkestad, L., Harslof, T., Brixen, K., Langdahl, B., 2017. Health-related quality of life in adults with osteogenesis imperfecta. Calcif. Tissue Int. 101, 473e478. Hegazy, A., Kenawey, M., Sochett, E., Tile, L., Cheung, A.M., Howard, A.W., 2016. Unusual femur stress fractures in children with osteogenesis imperfecta and intramedullary rods on long-term intravenous pamidronate therapy. J. Pediatr. Orthop. 36, 757e761. Herrmann, A.K., Grimm, D., 2018. High-throughput dissection of AAV-host interactions: the fast and the curious. J. Mol. Biol. 430, 2626e2640. Hiligsmann, M., Williams, S.A., Fitzpatrick, L.A., Silverman, S.S., Weiss, R., Reginster, J.Y., 2019. Cost-effectiveness of sequential treatment with abaloparatide vs. teriparatide for United States women at increased risk of fracture. Semin. Arthritis Rheum. https://doi.org/10.1016/j.semarthrit.2019.01.006. PMID 30737062. Homan, E.P., Rauch, F., Grafe, I., Lietman, C., Doll, J.A., Dawson, B., Bertin, T., Napierala, D., Morello, R., Gibbs, R., White, L., Miki, R., Cohn, D.H., Crawford, S., Travers, R., Glorieux, F.H., Lee, B., 2011. Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J. Bone Miner. Res. 26, 2798e2803. Horwitz, E.M., Dominici, M., 2008. How do mesenchymal stromal cells exert their therapeutic benefit? Cytotherapy 10, 771e774. Horwitz, E.M., Gordon, P.L., Koo, W.K., Marx, J.C., Neel, M.D., McNall, R.Y., Muul, L., Hofmann, T., 2002. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc. Natl. Acad. Sci. U. S. A 99, 8932e8937.

Osteogenesis imperfecta Chapter | 61

1501

Horwitz, E.M., Prockop, D.J., Fitzpatrick, L.A., Koo, W.W., Gordon, P.L., Neel, M., Sussman, M., Orchard, P., Marx, J.C., Pyeritz, R.E., Brenner, M.K., 1999. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 5, 309e313. Hoyer-Kuhn, H., Franklin, J., Allo, G., Kron, M., Netzer, C., Eysel, P., Hero, B., Schoenau, E., Semler, O., 2016. Safety and efficacy of denosumab in children with osteogenesis imperfect–a first prospective trial. J. Musculoskelet. Neuronal Interact. 16, 24e32. Jabbour, Z., Al-Khateeb, A., Eimar, H., Retrouvey, J.M., Rizkallah, J., Glorieux, F.H., Rauch, F., Tamimi, F., 2018. Genotype and malocclusion in patients with osteogenesis imperfecta. Orthod. Craniofac. Res. 21, 71e77. Jacobsen, C.M., Schwartz, M.A., Roberts, H.J., Lim, K.E., Spevak, L., Boskey, A.L., Zurakowski, D., Robling, A.G., Warman, M.L., 2016. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(þ/mov13) mouse model of type I Osteogenesis Imperfecta. Bone 90, 127e132. Jain, M., Tam, A., Shapiro, J.R., Steiner, R.D., Smith, P.A., Bober, M.B., Hart, T., Cuthbertson, D., Krischer, J., Mullins, M., Bellur, S., Byers, P.H., Pepin, M., Durigova, M., Glorieux, F.H., Rauch, F., Lee, B., Sutton, V.R., Members of the Brittle Bone Disorders Consortium, Nagamani, S.C.S., 2019. Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet. Med. 21, 275e283. Janus, G.J., Engelbert, R.H., Beek, E., Gooskens, R.H., Pruijs, J.E., 2003. Osteogenesis imperfecta in childhood: MR imaging of basilar impression. Eur. J. Radiol. 47, 19e24. Jasuja, R., Ge, G., Voss, N.G., Lyman-Gingerich, J., Branam, A.M., Pelegri, F.J., Greenspan, D.S., 2007. Bone morphogenetic protein 1 prodomain specifically binds and regulates signaling by bone morphogenetic proteins 2 and 4. J. Biol. Chem. 282, 9053e9062. Jepsen, K.J., Schaffler, M.B., Kuhn, J.L., Goulet, R.W., Bonadio, J., Goldstein, S.A., 1997. Type I collagen mutation alters the strength and fatigue behavior of Mov13 cortical tissue. J. Biomech. 30, 1141e1147. Kalajzic, I., Terzic, J., Rumboldt, Z., Mack, K., Naprta, A., Ledgard, F., Gronowicz, G., Clark, S.H., Rowe, D.W., 2002. Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse. Endocrinology 143, 1594e1601. Kang, H., Aryal, A.C.S., Marini, J.C., 2017. Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia. Transl. Res. 181, 27e48. Kelley, B.P., Malfait, F., Bonafe, L., Baldridge, D., Homan, E., Symoens, S., Willaert, A., Elcioglu, N., Van Maldergem, L., Verellen-Dumoulin, C., Gillerot, Y., Napierala, D., Krakow, D., Beighton, P., Superti-Furga, A., De Paepe, A., Lee, B., 2011. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J. Bone Miner. Res. 26, 666e672. Khandanpour, N., Connolly, D.J., Raghavan, A., Griffiths, P.D., Hoggard, N., 2012. Craniospinal abnormalities and neurologic complications of osteogenesis imperfecta: imaging overview. Radiographics 32, 2101e2112. Kilpinen, H., Goncalves, A., Leha, A., Afzal, V., Alasoo, K., Ashford, S., Bala, S., Bensaddek, D., Casale, F.P., Culley, O.J., Danecek, P., Faulconbridge, A., Harrison, P.W., Kathuria, A., McCarthy, D., McCarthy, S.A., Meleckyte, R., Memari, Y., Moens, N., Soares, F., Mann, A., Streeter, I., Agu, C.A., Alderton, A., Nelson, R., Harper, S., Patel, M., White, A., Patel, S.R., Clarke, L., Halai, R., Kirton, C.M., KolbKokocinski, A., Beales, P., Birney, E., Danovi, D., Lamond, A.I., Ouwehand, W.H., Vallier, L., Watt, F.M., Durbin, R., Stegle, O., Gaffney, D.J., 2017. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature 546, 370e375. Kovero, O., Pynnonen, S., Kuurila-Svahn, K., Kaitila, I., Waltimo-Siren, J., 2006. Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers. J. Neurosurg. 105, 361e370. Kuznetsova, N.V., McBride, D.J., Leikin, S., 2003. Changes in thermal stability and microunfolding pattern of collagen helix resulting from the loss of alpha2(I) chain in osteogenesis imperfecta murine. J. Mol. Biol. 331, 191e200. Lapunzina, P., Aglan, M., Temtamy, S., Caparros-Martin, J.A., Valencia, M., Leton, R., Martinez-Glez, V., Elhossini, R., Amr, K., Vilaboa, N., RuizPerez, V.L., 2010. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am. J. Hum. Genet. 87, 110e114. Le Blanc, K., Gotherstrom, C., Ringden, O., Hassan, M., McMahon, R., Horwitz, E., Anneren, G., Axelsson, O., Nunn, J., Ewald, U., NordenLindeberg, S., Jansson, M., Dalton, A., Astrom, E., Westgren, M., 2005. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 79, 1607e1614. Le, Q.A., Hay, J.W., Becker, R., Wang, Y., 2019. Cost-effectiveness analysis of sequential treatment of abaloparatide followed by alendronate versus teriparatide followed by alendronate in postmenopausal women with osteoporosis in the United States. Ann. Pharmacother. 53, 134e143. Leal, G.F., Nishimura, G., Voss, U., Bertola, D.R., Astrom, E., Svensson, J., Yamamoto, G.L., Hammarsjo, A., Horemuzova, E., Papadiogannakis, N., Iwarsson, E., Grigelioniene, G., Tham, E., 2018. Expanding the clinical spectrum of phenotypes caused by pathogenic variants in PLOD2. J. Bone Miner. Res. 33, 753e760. Leali, P.T., Balsano, M., Maestretti, G., Brusoni, M., Amorese, V., Ciurlia, E., Andreozzi, M., Caggiari, G., Doria, C., 2017. Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study. Clin. Cases Miner. Bone Metab. 14, 153e156. Lee, L.R., Peacock, L., Ginn, S.L., Cantrill, L.C., Cheng, T.L., Little, D.G., Munns, C.F., Schindeler, A., 2019. Bone marrow transplantation for treatment of the col1a2(þ/G610C) osteogenesis imperfecta mouse model. Calcif. Tissue Int. 104, 426e436. Lee, Y.S., Huynh, T.V., Lee, S.J., 2016. Paracrine and endocrine modes of myostatin action. J. Appl. Physiol. 120, 592e598. Li, H., Jiang, X., Delaney, J., Franceschetti, T., Bilic-Curcic, I., Kalinovsky, J., Lorenzo, J.A., Grcevic, D., Rowe, D.W., Kalajzic, I., 2010. Immature osteoblast lineage cells increase osteoclastogenesis in osteogenesis imperfecta murine. Am. J. Pathol. 176, 2405e2413. Lim, J., Grafe, I., Alexander, S., Lee, B., 2017. Genetic causes and mechanisms of osteogenesis imperfecta. Bone 102, 40e49.

1502 PART | II Molecular mechanisms of metabolic bone disease

Lindert, U., Weis, M.A., Rai, J., Seeliger, F., Hausser, I., Leeb, T., Eyre, D., Rohrbach, M., Giunta, C., 2015. Molecular consequences of the SERPINH1/ HSP47 mutation in the dachshund natural model of osteogenesis imperfecta. J. Biol. Chem. 290, 17679e17689. Liu, G., Chen, J., Zhou, Y., Zuo, Y., Liu, S., Chen, W., Wu, Z., Wu, N., 2017. The genetic implication of scoliosis in osteogenesis imperfecta: a review. J. Spine Surg. 3, 666e678. LoMauro, A., Fraschini, P., Pochintesta, S., Romei, M., D’Angelo, M.G., Aliverti, A., 2018. Ribcage deformity and the altered breathing pattern in children with osteogenesis imperfecta. Pediatr. Pulmonol. 53, 964e972. Lv, F., Xu, X., Song, Y., Li, L., Asan, Wang, J., Yang, H., Wang, O., Jiang, Y., Xia, W., Xing, X., Li, M., 2018. Novel mutations in PLOD2 cause rare Bruck syndrome. Calcif. Tissue Int. 102, 296e309. Lykke-Andersen, S., Jensen, T.H., 2015. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat. Rev. Mol. Cell Biol. 16, 665e677. Makino, A., Takagi, H., Takahashi, Y., Hase, N., Sugiyama, H., Yamana, K., Kobayashi, T., 2018. Abaloparatide exerts bone anabolic effects with less stimulation of bone resorption-related factors: a comparison with teriparatide. Calcif. Tissue Int. 103, 289e297. Makitie, R.E., Kampe, A.J., Taylan, F., Makitie, O., 2017. Recent discoveries in monogenic disorders of childhood bone fragility. Curr. Osteoporos. Rep. 15, 303e310. Malmgren, B., Andersson, K., Lindahl, K., Kindmark, A., Grigelioniene, G., Zachariadis, V., Dahllof, G., Astrom, E., 2017. Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes. Oral Dis. 23, 42e49. Marini, J.C., Forlino, A., Bachinger, H.P., Bishop, N.J., Byers, P.H., Paepe, A., Fassier, F., Fratzl-Zelman, N., Kozloff, K.M., Krakow, D., Montpetit, K., Semler, O., 2017. Osteogenesis imperfecta. Nat. Rev. Dis. Primers 3, 17052. Marini, J.C., Forlino, A., Cabral, W.A., Barnes, A.M., San Antonio, J.D., Milgrom, S., Hyland, J.C., Korkko, J., Prockop, D.J., De Paepe, A., Coucke, P., Symoens, S., Glorieux, F.H., Roughley, P.J., Lund, A.M., Kuurila-Svahn, K., Hartikka, H., Cohn, D.H., Krakow, D., Mottes, M., Schwarze, U., Chen, D., Yang, K., Kuslich, C., Troendle, J., Dalgleish, R., Byers, P.H., 2007. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum. Mutat. 28, 209e221. Marshall, C., Lopez, J., Crookes, L., Pollitt, R.C., Balasubramanian, M., 2016. A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly. Gene 595, 49e52. Matic, I., Matthews, B.G., Wang, X., Dyment, N.A., Worthley, D.L., Rowe, D.W., Grcevic, D., Kalajzic, I., 2016. Quiescent bone lining cells are a major source of osteoblasts during adulthood. Stem Cells 34, 2930e2942. Matthews, B.G., Roeder, E., Wang, X., Aguila, H.L., Lee, S.K., Grcevic, D., Kalajzic, I., 2017. Splenomegaly, myeloid lineage expansion and increased osteoclastogenesis in osteogenesis imperfecta murine. Bone 103, 1e11. McPherron, A.C., Lawler, A.M., Lee, S.J., 1997. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83e90. Mendoza-Londono, R., Fahiminiya, S., Majewski, J., Consortium Care4Rare Canada, Tetreault, M., Nadaf, J., Kannu, P., Sochett, E., Howard, A., Stimec, J., Dupuis, L., Roschger, P., Klaushofer, K., Palomo, T., Ouellet, J., Al-Jallad, H., Mort, J.S., Moffatt, P., Boudko, S., Bachinger, H.P., Rauch, F., 2015. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am. J. Hum. Genet. 96, 979e985. Michalczyk, E.R., Chen, L., Fine, D., Zhao, Y., Mascarinas, E., Grippo, P.J., DiPietro, L.A., 2018. Pigment epithelium-derived factor (PEDF) as a regulator of wound angiogenesis. Sci. Rep. 8, 11142. Migliaccio, S., Barbaro, G., Fornari, R., Di Lorenzo, G., Celli, M., Lubrano, C., Falcone, S., Fabbrini, E., Greco, E., Zambrano, A., Brama, M., Prossomariti, G., Marzano, S., Marini, M., Conti, F., D’Eufemia, P., Spera, G., 2009. Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality? Int. J. Cardiol. 131, 200e203. Millard, S.M., Pettit, A.R., Ellis, R., Chan, J.K., Raggatt, L.J., Khosrotehrani, K., Fisk, N.M., 2015. Intrauterine bone marrow transplantation in osteogenesis imperfecta mice yields donor osteoclasts and osteomacs but not osteoblasts. Stem Cell Reports 5, 682e689. Mirigian, L.S., Makareeva, E., Mertz, E.L., Omari, S., Roberts-Pilgrim, A.M., Oestreich, A.K., Phillips, C.L., Leikin, S., 2016. Osteoblast malfunction caused by cell stress response to procollagen misfolding in alpha2(I)-G610C mouse model of osteogenesis imperfecta. J. Bone Miner. Res. 31, 1608e1616. Montpetit, K., Palomo, T., Glorieux, F.H., Fassier, F., Rauch, F., 2015. Multidisciplinary treatment of severe osteogenesis imperfecta: functional outcomes at skeletal maturity. Arch. Phys. Med. Rehabil. 96, 1834e1839. Morello, R., 2018. Osteogenesis imperfecta and therapeutics. Matrix Biol. 71e72, 294e312. Muir, A.M., Massoudi, D., Nguyen, N., Keene, D.R., Lee, S.J., Birk, D.E., Davidson, J.M., Marinkovich, M.P., Greenspan, D.S., 2016. BMP1-like proteinases are essential to the structure and wound healing of skin. Matrix Biol. 56, 114e131. Muir, A.M., Ren, Y., Butz, D.H., Davis, N.A., Blank, R.D., Birk, D.E., Lee, S.J., Rowe, D., Feng, J.Q., Greenspan, D.S., 2014. Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum. Mol. Genet. 23, 3085e3101. Najirad, M., Ma, M.S., Rauch, F., Sutton, V.R., Lee, B., Retrouvey, J.M., Members of the, B.B.D., Esfandiari, S., 2018. Oral health-related quality of life in children and adolescents with osteogenesis imperfecta: cross-sectional study. Orphanet J. Rare Dis. 13, 187. Nguyen, M.S., Binh, H.D., Nguyen, K.M., Maasalu, K., Koks, S., Martson, A., Saag, M., Jagomagi, T., 2017. Occlusal features and need for orthodontic treatment in persons with osteogenesis imperfecta. Clin. Exp. Dent. Res. 3, 19e24. Nicol, L., Morar, P., Wang, Y., Henriksen, K., Sun, S., Karsdal, M., Smith, R., Nagamani, S.C.S., Shapiro, J., Lee, B., Orwoll, E., 2019. Alterations in non-type I collagen biomarkers in osteogenesis imperfecta. Bone 120, 70e74.

Osteogenesis imperfecta Chapter | 61

1503

Nicol, L., Wang, Y., Smith, R., Sloan, J., Nagamani, S.C., Shapiro, J., Lee, B., Orwoll, E., 2018. Serum sclerostin levels in adults with osteogenesis imperfecta: comparison with normal individuals and response to teriparatide therapy. J. Bone Miner. Res. 33, 307e315. Nicolaou, N., Agrawal, Y., Padman, M., Fernandes, J.A., Bell, M.J., 2012. Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates. J. Child. Orthopaed. 6, 21e27. NORD, 2019. National Organization for Rare Diseases. https://rarediseases.org. O’Donnell, C., Bloch, N., Michael, N., Erickson, M., Garg, S., 2017. Management of scoliosis in children with osteogenesis imperfecta. JBJS Rev. 5, e8. Oestreich, A.K., Carleton, S.M., Yao, X., Gentry, B.A., Raw, C.E., Brown, M., Pfeiffer, F.M., Wang, Y., Phillips, C.L., 2016. Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice. Osteoporos. Int. 27, 161e170. OIF, 2019. Osteogenesis Imperfecta Foundation. http://www.oif.org/site/PageServer. OIF-Testing, 2019. Genetic Testing for OI. http://www.oif.org/site/PageServer?pagename¼Testing. Olvera, D., Stolzenfeld, R., Marini, J.C., Caird, M.S., Kozloff, K.M., 2018. Low dose of bisphosphonate enhances sclerostin antibody-induced trabecular bone mass Gains in Brtl/þ osteogenesis imperfecta mouse model. J. Bone Miner. Res. 33, 1272e1282. Omata, Y., Nakamura, S., Koyama, T., Yasui, T., Hirose, J., Izawa, N., Matsumoto, T., Imai, Y., Seo, S., Kurokawa, M., Tsutsumi, S., Kadono, Y., Morimoto, C., Aburatani, H., Miyamoto, T., Tanaka, S., 2016. Identification of Nedd9 as a TGF-beta-Smad2/3 target gene involved in RANKLinduced osteoclastogenesis by comprehensive analysis. PLoS One 11, e0157992. Orwoll, E.S., Shapiro, J., Veith, S., Wang, Y., Lapidus, J., Vanek, C., Reeder, J.L., Keaveny, T.M., Lee, D.C., Mullins, M.A., Nagamani, S.C., Lee, B., 2014. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J. Clin. Investig. 124, 491e498. Otsuru, S., Overholt, K.M., Olson, T.S., Hofmann, T.J., Guess, A.J., Velazquez, V.M., Kaito, T., Dominici, M., Horwitz, E.M., 2017. Hematopoietic derived cells do not contribute to osteogenesis as osteoblasts. Bone 94, 1e9. Pace, J.M., Wiese, M., Drenguis, A.S., Kuznetsova, N., Leikin, S., Schwarze, U., Chen, D., Mooney, S.H., Unger, S., Byers, P.H., 2008. Defective Cpropeptides of the proalpha2(I) chain of type I procollagen impede molecular assembly and result in osteogenesis imperfecta. J. Biol. Chem. 283, 16061e16067. Pai, A.A., Pritchard, J.K., Gilad, Y., 2015. The genetic and mechanistic basis for variation in gene regulation. PLoS Genet. 11, e1004857. Palomo, T., Al-Jallad, H., Moffatt, P., Glorieux, F.H., Lentle, B., Roschger, P., Klaushofer, K., Rauch, F., 2014. Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations. Bone 67, 63e70. Palomo, T., Fassier, F., Ouellet, J., Sato, A., Montpetit, K., Glorieux, F.H., Rauch, F., 2015. Intravenous bisphosphonate therapy of young children with osteogenesis imperfecta: skeletal findings during follow up throughout the growing years. J. Bone Miner. Res. 30, 2150e2157. Panigrahi, I., Didel, S., Kirpal, H., Bellampalli, R., Miyanath, S., Mullapudi, N., Rao, S., 2018. Novel mutation in a family with WNT1-related osteoporosis. Eur. J. Med. Genet. 61, 369e371. Pauley, P., Matthews, B.G., Wang, L., Dyment, N.A., Matic, I., Rowe, D.W., Kalajzic, I., 2014. Local transplantation is an effective method for cell delivery in the osteogenesis imperfecta murine model. Int. Orthop. 38, 1955e1962. Pavone, V., Mattina, T., Pavone, P., Falsaperla, R., Testa, G., 2017. Early motor delay: an outstanding, initial Sign of osteogenesis imperfecta type 1. J. Orthop. Case Rep. 7, 63e66. Piantoni, L., Noel, M.A., Francheri Wilson, I.A., Tello, C.A., Galaretto, E., Remondino, R.G., Bersusky, E.S., 2017. Surgical treatment with pedicle Screws of scoliosis associated with osteogenesis imperfecta in children. Spine Deform 5, 360e365. Pollitt, R.C., Saraff, V., Dalton, A., Webb, E.A., Shaw, N.J., Sobey, G.J., Mughal, M.Z., Hobson, E., Ali, F., Bishop, N.J., Arundel, P., Hogler, W., Balasubramanian, M., 2016. Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations. Am. J. Med. Genet. 170, 3150e3156. Pouliot-Laforte, A., Veilleux, L.N., Rauch, F., Lemay, M., 2015. Physical activity in youth with osteogenesis imperfecta type I. J. Musculoskelet. Neuronal Interact. 15, 171e176. Pyott, S.M., Pepin, M.G., Schwarze, U., Yang, K., Smith, G., Byers, P.H., 2011. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet. Med. 13, 125e130. Radunovic, Z., Steine, K., 2015. Prevalence of cardiovascular disease and cardiac symptoms: left and right ventricular function in adults with osteogenesis imperfecta. Can. J. Cardiol. 31, 1386e1392. Radunovic, Z., Wekre, L.L., Diep, L.M., Steine, K., 2011. Cardiovascular abnormalities in adults with osteogenesis imperfecta. Am. Heart J. 161, 523e529. Ramirez, F., Caescu, C., Wondimu, E., Galatioto, J., 2018. Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFbeta signaling and cell stemness. Matrix Biol. 71-72, 82e89. Rauch, F., Fahiminiya, S., Majewski, J., Carrot-Zhang, J., Boudko, S., Glorieux, F., Mort, J.S., Bachinger, H.P., Moffatt, P., 2015. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am. J. Hum. Genet. 96, 425e431. Rauch, F., Geng, Y., Lamplugh, L., Hekmatnejad, B., Gaumond, M.H., Penney, J., Yamanaka, Y., Moffatt, P., 2018. Crispr-Cas9 engineered osteogenesis imperfecta type V leads to severe skeletal deformities and perinatal lethality in mice. Bone 107, 131e142. Rauch, F., Husseini, A., Roughley, P., Glorieux, F.H., Moffatt, P., 2012. Lack of circulating pigment epithelium-derived factor is a marker of osteogenesis imperfecta type VI. J. Clin. Endocrinol. Metab. 97, E1550eE1556. Rauch, F., Lalic, L., Roughley, P., Glorieux, F.H., 2010. Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J. Bone Miner. Res. 25, 1367e1374. Rauch, F., Moffatt, P., Cheung, M., Roughley, P., Lalic, L., Lund, A.M., Ramirez, N., Fahiminiya, S., Majewski, J., Glorieux, F.H., 2013. Osteogenesis imperfecta type V: marked phenotypic variability despite the presence of the IFITM5 c.-14C>T mutation in all patients. J. Med. Genet. 50, 21e24.

1504 PART | II Molecular mechanisms of metabolic bone disease

Rauch, F., Travers, R., Glorieux, F.H., 2006. Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy. J. Clin. Endocrinol. Metab. 91, 511e516. RDCRN, 2019. Rare Diseases Clinical Research Network. https://ncats.nih.gov/rdcrn. Retrouvey, J.M., Taqi, D., Tamimi, F., Dagdeviren, D., Glorieux, F.H., Lee, B., Hazboun, R., Krakow, D., Sutton, V.R., Consortium Members of the, B.B.D., 2018. Oro-dental and cranio-facial characteristics of osteogenesis imperfecta type V. Eur. J. Med. Genet. https://doi.org/10.1016/ j.ejmg.2018.12.011. Rosset, E.M., Bradshaw, A.D., 2016. SPARC/osteonectin in mineralized tissue. Matrix Biol. 52e54, 78e87. Rothschild, L., Goeller, J.K., Voronov, P., Barabanova, A., Smith, P., 2018. Anesthesia in children with osteogenesis imperfecta: retrospective chart review of 83 patients and 205 anesthetics over 7 years. Paediatr. Anaesth. 28, 1050e1058. Rowe, D.W., Shapiro, J.R., Poirier, M., Schlesinger, S., 1985. Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta. J. Clin. Investig. 76, 604e611. Rowe, R.G., Daley, G.Q., 2019. Induced pluripotent stem cells in disease modelling and drug discovery. Nat. Rev. Genet. https://doi.org/10.1038/s41576019-0100-z. Ruck, J., Dahan-Oliel, N., Montpetit, K., Rauch, F., Fassier, F., 2011. Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J. Child. Orthopaed. 5, 217e224. Rush, E.T., Li, L., Goodwin, J.L., Kreikemeier, R.M., Craft, M., Danford, D.A., Kutty, S., 2017. Echocardiographic phenotype in osteogenesis imperfecta varies with disease severity. Heart 103, 443e448. Scheiber, A.L., Guess, A.J., Kaito, T., Abzug, J.M., Enomoto-Iwamoto, M., Leikin, S., Iwamoto, M., Otsuru, S., 2019. Endoplasmic reticulum stress is induced in growth plate hypertrophic chondrocytes in G610C mouse model of osteogenesis imperfecta. Biochem. Biophys. Res. Commun. 509, 235e240. Schwarze, U., Hata, R., McKusick, V.A., Shinkai, H., Hoyme, H.E., Pyeritz, R.E., Byers, P.H., 2004. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am. J. Hum. Genet. 74, 917e930. Shapiro, F., 1985. Consequences of an osteogenesis imperfecta diagnosis for survival and ambulation. J. Pediatr. Orthop. 5, 456e462. Shapiro, J.R., Burn, V.E., Chipman, S.D., Jacobs, J.B., Schloo, B., Reid, L., Larsen, N., Louis, F., 1989. Pulmonary hypoplasia and osteogenesis imperfecta type II with defective synthesis of alpha I(1) procollagen. Bone 10, 165e171. Shapiro, J.R., Lietman, C., Grover, M., Lu, J.T., Nagamani, S.C., Dawson, B.C., Baldridge, D.M., Bainbridge, M.N., Cohn, D.H., Blazo, M., Roberts, T.T., Brennen, F.S., Wu, Y., Gibbs, R.A., Melvin, P., Campeau, P.M., Lee, B.H., 2013. Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation. J. Bone Miner. Res. 28, 1523e1530. Sinder, B.P., Lloyd, W.R., Salemi, J.D., Marini, J.C., Caird, M.S., Morris, M.D., Kozloff, K.M., 2016. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age. Bone 84, 222e229. Sinikumpu, J.J., Ojaniemi, M., Lehenkari, P., Serlo, W., 2015. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review. Injury 46, 1440e1446. Song, Y., Zhao, D., Xu, X., Lv, F., Li, L., Jiang, Y., Wang, O., Xia, W., Xing, X., Li, M., 2018. Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X. Osteoporos. Int. 29, 1389e1396. Sridharan, K., Sivaramakrishnan, G., 2018. Interventions for improving bone mineral density and reducing fracture risk in osteogenesis imperfecta: a mixed treatment comparison Network meta-analysis of randomized controlled clinical trials. Curr. Clin. Pharmacol. 13, 190e198. Suzumori, N., Hasegawa, T., Sugiura-Ogasawara, M., 2011. Prenatal diagnosis of osteogenesis imperfecta type II by three-dimensional ultrasound and computed tomography. J. Obstet. Gynaecol. Res. 37, 664e665. Swezey, T., Reeve, B.B., Hart, T.S., Floor, M.K., Dollar, C.M., Gillies, A.P., Tosi, L.L., 2019. Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community. Osteoporos. Int. 30, 507e511. Syx, D., Guillemyn, B., Symoens, S., Sousa, A.B., Medeira, A., Whiteford, M., Hermanns-Le, T., Coucke, P.J., De Paepe, A., Malfait, F., 2015. Defective proteolytic processing of fibrillar procollagens and prodecorin due to Biallelic BMP1 mutations results in a severe, progressive form of osteogenesis imperfecta. J. Bone Miner. Res. 30, 1445e1456. Tabebordbar, M., Zhu, K., Cheng, J.K.W., Chew, W.L., Widrick, J.J., Yan, W.X., Maesner, C., Wu, E.Y., Xiao, R., Ran, F.A., Cong, L., Zhang, F., Vandenberghe, L.H., Church, G.M., Wagers, A.J., 2016. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407e411. Tam, A., Chen, S., Schauer, E., Grafe, I., Bandi, V., Shapiro, J.R., Steiner, R.D., Smith, P.A., Bober, M.B., Hart, T., Cuthbertson, D., Krischer, J., Mullins, M., Byers, P.H., Sandhaus, R.A., Durigova, M., Glorieux, F.H., Rauch, F., Reid Sutton, V., Lee, B., Consortium Members of the Brittle Bone Disorders, Rush, E.T., Nagamani, S.C.S., 2018. A multicenter study to evaluate pulmonary function in osteogenesis imperfecta. Clin. Genet. 94, 502e511. Thuesen, K.J., Gjorup, H., Hald, J.D., Schmidt, M., Harslof, T., Langdahl, B., Haubek, D., 2018. The dental perspective on osteogenesis imperfecta in a Danish adult population. BMC Oral Health 18, 175. Trejo, P., Fassier, F., Glorieux, F.H., Rauch, F., 2017a. Diaphyseal femur fractures in osteogenesis imperfecta: characteristics and relationship with bisphosphonate treatment. J. Bone Miner. Res. 32, 1034e1039. Trejo, P., Palomo, T., Montpetit, K., Fassier, F., Sato, A., Glorieux, F.H., Rauch, F., 2017b. Long-term follow-up in osteogenesis imperfecta type VI. Osteoporos. Int. 28, 2975e2983.

Osteogenesis imperfecta Chapter | 61

1505

Tsimicalis, A., Boitor, M., Ferland, C.E., Rauch, F., Le May, S., Carrier, J.I., Ngheim, T., Bilodeau, C., 2018. Pain and quality of life of children and adolescents with osteogenesis imperfecta over a bisphosphonate treatment cycle. Eur. J. Pediatr. 177, 891e902. Ulla, M., Aiello, H., Cobos, M.P., Orioli, I., Garcia-Monaco, R., Etchegaray, A., Igarzabal, M.L., Otano, L., 2011. Prenatal diagnosis of skeletal dysplasias: contribution of three-dimensional computed tomography. Fetal Diagn. Ther. 29, 238e247. Veilleux, L.N., Lemay, M., Pouliot-Laforte, A., Cheung, M.S., Glorieux, F.H., Rauch, F., 2014. Muscle anatomy and dynamic muscle function in osteogenesis imperfecta type I. J. Clin. Endocrinol. Metab. 99, E356eE362. Volodarsky, M., Markus, B., Cohen, I., Staretz-Chacham, O., Flusser, H., Landau, D., Shelef, I., Langer, Y., Birk, O.S., 2013. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum. Mutat. 34, 582e586. Wallace, M.J., Kruse, R.W., Shah, S.A., 2017. The spine in patients with osteogenesis imperfecta. J. Am. Acad. Orthop. Surg. 25, 100e109. Wang, J.Y., Liu, Y., Song, L.J., Lv, F., Xu, X.J., San, A., Wang, J., Yang, H.M., Yang, Z.Y., Jiang, Y., Wang, O., Xia, W.B., Xing, X.P., Li, M., 2017. Novel mutations in SERPINF1 result in rare osteogenesis imperfecta type VI. Calcif. Tissue Int. 100, 55e66. Wang, L., Liu, Y., Kalajzic, Z., Jiang, X., Rowe, D.W., 2005. Heterogeneity of engrafted bone-lining cells after systemic and local transplantation. Blood 106, 3650e3657. Ward, L.M., Rauch, F., Whyte, M.P., D’Astous, J., Gates, P.E., Grogan, D., Lester, E.L., McCall, R.E., Pressly, T.A., Sanders, J.O., Smith, P.A., Steiner, R.D., Sullivan, E., Tyerman, G., Smith-Wright, D.L., Verbruggen, N., Heyden, N., Lombardi, A., Glorieux, F.H., 2011. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J. Clin. Endocrinol. Metab. 96, 355e364. Webb, E.A., Balasubramanian, M., Fratzl-Zelman, N., Cabral, W.A., Titheradge, H., Alsaedi, A., Saraff, V., Vogt, J., Cole, T., Stewart, S., Crabtree, N.J., Sargent, B.M., Gamsjaeger, S., Paschalis, E.P., Roschger, P., Klaushofer, K., Shaw, N.J., Marini, J.C., Hogler, W., 2017. Phenotypic spectrum in osteogenesis imperfecta due to mutations in TMEM38B: unraveling a complex cellular defect. J. Clin. Endocrinol. Metab. 102, 2019e2028. Westgren, M., Gotherstrom, C., 2015. Stem cell transplantation before birth - a realistic option for treatment of osteogenesis imperfecta? Prenat. Diagn. 35, 827e832. Wright, N.M., 2000. Just taller or more bone? The impact of growth hormone on osteogenesis imperfecta and idiopathic juvenile osteoporosis. J. Pediatr. Endocrinol. Metab. 13 (Suppl. 2), 999e1002. Xin, X., Kronenberg, M., Chen, L., Wu, Z., Wang, L., Jiang, X., Rowe, D.W., Lichtler, A., 2017. Mutation Correction in OI iPSCs Restores Bone Formation. http://www.asbmr.org/education/AbstractDetail?aid¼47690120-1c03-4151-a399-7ea0b7bab156. Xin, X., Kronenberg, M., Lichtler, A., Rowe, D.W., 2018a. Continued development of hiPSCs as an in vivo platform for exploring heritable disorders of the human skeleton. J. Bone Miner. Res. 33. Xin, X., Jiang, X., Lichtler, A., Kronenberg, M., Rowe, D., Pachter, J.S., 2018b. Laser-capture microdissection and RNA extraction from perfusion-fixed cartilage and bone tissue from mice implanted with human iPSC-derived MSCs in a calvarial defect model. Methods Mol. Biol. 1723, 385e396. Xu, X.J., Lv, F., Song, Y.W., Li, L.J., Asan, Wei, X.X., Zhao, X.L., Jiang, Y., Wang, O., Xing, X.P., Xia, W.B., Li, M., 2019. Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. Clin. Chim. Acta 489, 21e28. Yamagishi, S., Matsui, T., Nakamura, K., Takenaka, K., 2010. Pigment epithelium-derived factor (PEDF) inhibits collagen-induced platelet activation by reducing intraplatelet nitrotyrosine levels. Int. J. Cardiol. 140, 121e122. Yasui, T., Kadono, Y., Nakamura, M., Oshima, Y., Matsumoto, T., Masuda, H., Hirose, J., Omata, Y., Yasuda, H., Imamura, T., Nakamura, K., Tanaka, S., 2011. Regulation of RANKL-induced osteoclastogenesis by TGF-beta through molecular interaction between Smad3 and Traf6. J. Bone Miner. Res. 26, 1447e1456. Zack, P., Franck, L., Devile, C., Clark, C., 2005. Fracture and non-fracture pain in children with osteogenesis imperfecta. Acta Paediatr. 94, 1238e1242. Zhang, Z.L., Zhang, H., Ke, Y.H., Yue, H., Xiao, W.J., Yu, J.B., Gu, J.M., Hu, W.W., Wang, C., He, J.W., Fu, W.Z., 2012. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J. Bone Miner. Metab. 30, 69e77. Zimmerman, S.M., Heard-Lipsmeyer, M.E., Dimori, M., Thostenson, J.D., Mannen, E.M., O’Brien, C.A., Morello, R., 2018. Loss of RANKL in osteocytes dramatically increases cancellous bone mass in the osteogenesis imperfecta mouse (oim). Bone Rep. 9, 61e73.

Further reading Treatment, O.I.F., 2017. Treatment Recommendation from OIF. http://www.oif.org/site/PageServer?pagename¼oif_mc_home_page.