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Osteogenesis imperfecta: Bench to bedside
Conference Proceedings
identification of the causative gene in FOP, together with the development of in vivo and in vitro models for heterotopic ossification and mesenchymal cell differentiation, is providing opportunities to understand the cellular and molecular mechanisms that regulate chondrogenesis and osteogenesis and control the pathological induction of heterotopic bone formation. This knowledge will lead to novel approaches to modulate BMP signaling and bone formation and to the development of treatments for FOP and other disorders of bone and cartilage.
X-Linked Hypophosphatasia Syndromes (XLH): Update on XLH Research; Gaps in Knowledge . . . By Michael Econs, MD; Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN
Abstract Not Received
Pathogenesis of MHE: Recent Advances and Prospects For Therapies . . . By Maurizio Pacifici, PhD; Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA
Multiple hereditary exostoses (MHE) is a congenital autosomal-dominant disorder caused by mutations in the Golgi-associated heparan sulfate (HS)-synthesizing enzymes, EXT1 or EXT2, leading to HS deficiency throughout the body. The disease is characterized by the presence of exostoses (known also as osteochondromas) that are cartilage-capped outgrowths forming next to, but never within, the growth plates of limb and trunk skeletal elements. The exostoses interfere with growth plate function and the MHE children could display growth retardation and skeletal deformities, as well as chronic pain, impingement of nerves and tendons, urinary obstruction, or other symptoms. To elucidate the mechanisms of exostosis formation and growth, we have created mouse models in which Ext1 or Ext2 were ablated broadly or conditionally. We will describe published and unpublished data from our recent studies that provide insights into the genesis and preferential anatomical location of the exostoses in the growing skeleton. In particular, the data suggest that the exostoses are triggered by a redistribution and aberrant activation of prochondrogenic signaling proteins within the growth plate and/or adjacent perichondrium, with the possible involvement and recruitment of local progenitor cells including those in the groove of Ranvier. We will also present data from in vitro cellular studies that provide insights into underlying biochemical and molecular mechanisms. Our studies are leading to a better understanding of MHE pathogenesis and point to prospects for possible future therapies.
547 Osteogenesis Imperfecta: Bench to Bedside . . . By Jay R. Shapiro, MD, and Emily L. Germain-Lee, MD; The Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD
The Bench: There has been a significant expansion in our understanding of the molecular biology of OI. The number of genes responsible for the disorder has increased from 2 (COL1A1 and COL1A2) in 2007, to 9 in 2012 (CRTAP, LEPRE1, PPIB, Hsp47/SERPINH1, SERPINF1, FKBP10 and most recently, adding IFITM5). Also, there has been additional categorization of clinical OI types since Sillence first recognized 4 OI types in 1978. An issue is the nosology of OI: should that be based on each mutation or should a broad clinical classification be retained? Although multiple mutations have been defined, we have not progressed in our understanding of how each mutation translates to disordered bone and connective-tissue cell function. Although mutations alter osteoblast type I collagen synthesis, the effects on osteoblast cell biology, for example on cell growth, are undefined. The question of genotype/phenotype relationships is exemplified by the wide clinical variability seen in the phenotypic of OI type V where there is apparent consistency in expression of the mutation IFITM5 (genotype), among affected kindreds, more so than occurs in other OI types where multiple mutations are expressed in a particular OI phenotype. The Bedside: Two clinical issues which are interrelated are: (a) Understanding the pain syndrome in OI, and (b) the status of fracture prevention treatment for children and adults: this includes considerable variability among centers in drug selection (pamidronate vs. zoledronic acid), drug doses which vary from 4 to 9 mg/kg/year in children, and treatment schedules which vary from 4 to 6 months, particularly in children who have already had several years of treatment.
Gorham-Stout Disease and Generalized Lymphatic Anomalies . . . By Cameron C. Trenor III, MD, and Matthew L. Warman, MD; Vascular Anomalies Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA
We postulate that there exist two distinct lymphatic malformation disorders that affect bones and cause significant morbidity and mortality. Gorham-Stout disease (G-SD) is characterized by the progressive disappearance of trabecular and cortical bone. Generalized lymphatic anomaly (GLA) is characterized by missing areas within trabecular bone and sparing of cortical bone. It is likely that both diseases have a genetic etiology because they often affect multiple noncontiguous sites; however, neither disease is heritable. Both disorders cause focal skeletal fragility. Pleural, pericardial, and peritoneal effusions also frequently complicate these
identification of the causative gene in FOP, together with the development of in vivo and in vitro models for heterotopic ossification and mesenchymal cell differentiation, is providing opportunities to understand the cellular and molecular mechanisms that regulate chondrogenesis and osteogenesis and control the pathological induction of heterotopic bone formation. This knowledge will lead to novel approaches to modulate BMP signaling and bone formation and to the development of treatments for FOP and other disorders of bone and cartilage.
X-Linked Hypophosphatasia Syndromes (XLH): Update on XLH Research; Gaps in Knowledge . . . By Michael Econs, MD; Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN
Abstract Not Received
Pathogenesis of MHE: Recent Advances and Prospects For Therapies . . . By Maurizio Pacifici, PhD; Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA
Multiple hereditary exostoses (MHE) is a congenital autosomal-dominant disorder caused by mutations in the Golgi-associated heparan sulfate (HS)-synthesizing enzymes, EXT1 or EXT2, leading to HS deficiency throughout the body. The disease is characterized by the presence of exostoses (known also as osteochondromas) that are cartilage-capped outgrowths forming next to, but never within, the growth plates of limb and trunk skeletal elements. The exostoses interfere with growth plate function and the MHE children could display growth retardation and skeletal deformities, as well as chronic pain, impingement of nerves and tendons, urinary obstruction, or other symptoms. To elucidate the mechanisms of exostosis formation and growth, we have created mouse models in which Ext1 or Ext2 were ablated broadly or conditionally. We will describe published and unpublished data from our recent studies that provide insights into the genesis and preferential anatomical location of the exostoses in the growing skeleton. In particular, the data suggest that the exostoses are triggered by a redistribution and aberrant activation of prochondrogenic signaling proteins within the growth plate and/or adjacent perichondrium, with the possible involvement and recruitment of local progenitor cells including those in the groove of Ranvier. We will also present data from in vitro cellular studies that provide insights into underlying biochemical and molecular mechanisms. Our studies are leading to a better understanding of MHE pathogenesis and point to prospects for possible future therapies.
547 Osteogenesis Imperfecta: Bench to Bedside . . . By Jay R. Shapiro, MD, and Emily L. Germain-Lee, MD; The Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD
The Bench: There has been a significant expansion in our understanding of the molecular biology of OI. The number of genes responsible for the disorder has increased from 2 (COL1A1 and COL1A2) in 2007, to 9 in 2012 (CRTAP, LEPRE1, PPIB, Hsp47/SERPINH1, SERPINF1, FKBP10 and most recently, adding IFITM5). Also, there has been additional categorization of clinical OI types since Sillence first recognized 4 OI types in 1978. An issue is the nosology of OI: should that be based on each mutation or should a broad clinical classification be retained? Although multiple mutations have been defined, we have not progressed in our understanding of how each mutation translates to disordered bone and connective-tissue cell function. Although mutations alter osteoblast type I collagen synthesis, the effects on osteoblast cell biology, for example on cell growth, are undefined. The question of genotype/phenotype relationships is exemplified by the wide clinical variability seen in the phenotypic of OI type V where there is apparent consistency in expression of the mutation IFITM5 (genotype), among affected kindreds, more so than occurs in other OI types where multiple mutations are expressed in a particular OI phenotype. The Bedside: Two clinical issues which are interrelated are: (a) Understanding the pain syndrome in OI, and (b) the status of fracture prevention treatment for children and adults: this includes considerable variability among centers in drug selection (pamidronate vs. zoledronic acid), drug doses which vary from 4 to 9 mg/kg/year in children, and treatment schedules which vary from 4 to 6 months, particularly in children who have already had several years of treatment.
Gorham-Stout Disease and Generalized Lymphatic Anomalies . . . By Cameron C. Trenor III, MD, and Matthew L. Warman, MD; Vascular Anomalies Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA
We postulate that there exist two distinct lymphatic malformation disorders that affect bones and cause significant morbidity and mortality. Gorham-Stout disease (G-SD) is characterized by the progressive disappearance of trabecular and cortical bone. Generalized lymphatic anomaly (GLA) is characterized by missing areas within trabecular bone and sparing of cortical bone. It is likely that both diseases have a genetic etiology because they often affect multiple noncontiguous sites; however, neither disease is heritable. Both disorders cause focal skeletal fragility. Pleural, pericardial, and peritoneal effusions also frequently complicate these