Skeletal Growth Factors

Chapter 19

Skeletal Growth Factors Ernesto Canalis

I. II. III. IV. V.

I.

Introduction Platelet-Derived Growth Factor Vascular Endothelial Growth Factor Fibroblast Growth Factor Transforming Growth Factor Beta

INTRODUCTION

Bone formation and resorption are regulated by systemic and local factors acting in concert to maintain bone mass. Calciotropic and steroid hormones have been studied extensively for their effects on bone remodeling. However, there is compelling evidence to support the concept that systemic and locally produced growth factors play a central role in the regulation of bone remodeling. Growth factors regulate the replication, differentiation, and function of bone cells. This chapter will be limited to the description of factors that have a major effect on bone formation and osteoblastic function, whereas other chapters of this book will describe cytokines that regulate bone resorption. This is a somewhat arbitrary division since bone remodeling is coupled and osteoclastogenesis is highly dependent on osteoblastic signals. Furthermore, cytokines with primary effects on cells of the osteoclast lineage also play a role in the process of bone formation. Although skeletal cells synthesize a variety of factors, some skeletal growth factors, such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor β (TGF β), bone morphogenetic proteins (BMP), and insulin-like growth factors (IGF) have been studied in more detail. Some of these factors act as bone cell mitogens, and as such they are important in the maintenance of an adequate number of skeletal cells. They also may increase bone cell replication when additional cells are needed, such as during fracture healing and repair. A factor may play a role in the differentiation of cells and osteoblastogenesis, or may stimulate the differentiated function of mature cells. There are no growth factors specifically synthesized by skeletal cells, and those known as skeletal growth factors also are expressed in various nonskeletal tissues. However, growth factors are regulated specifically in bone at the level of synthesis or activity by agents that OSTEOPOROSIS, 3RD EDITION Marcus, Feldman, Nelson, and Rosen

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VI. VII. VIII. IX.

Bone Morphogenetic Protein Insulin-Like Growth Factor Insulin-Like Growth Factor Binding Proteins Hepatocyte Growth Factor Acknowledgments

act primarily on this tissue. Growth factors synthesized by skeletal cells may be present in the systemic circulation, and act both as local and systemic regulators of bone remodeling. The source of circulating growth factors varies, although it is frequently the liver, the circulating platelets, or peripheral tissues. The systemic form of a factor can be regulated by agents and mechanisms different from those affecting the locally produced factor, and it is conceivable that the roles of the circulating and local form of a growth factor differ. This is not only because their synthesis is regulated by different hormones, but also because they may become available under different physiological or pathophysiological circumstances. It is tempting to believe that the local form of a growth factor plays a more immediate, and possibly important role in the control of cell function since it has a more direct access to its target cell. Locally synthesized growth factors can act either as autocrine factors and affect cells of the same class, or paracrine factors and affect different or adjacent cells. In this chapter the function and regulation of selected growth factors will be discussed and their relevance to skeletal physiology will be considered.

II. PLATELET-DERIVED GROWTH FACTOR PDGF was originally isolated from human platelets, and four members of the pdgf gene family have been identified—pdgf a, pdgf b, pdgf c, and pdgf d [1]. VEGF shares a high degree of sequence homology with PDGF and these factors are often referred as members of the PDGF/VEGF family [2]. This family of genes encodes a highly conserved cystine knot motif. The recently discovered pdgf c and pdgf d genes have a Clr/ Cls, urchin endothelial growth factor, BMP l (CUB) domain linked to the cystine knot core motif by a hinge domain [3, 4, 5, 6]. Several reports have indicated that Copyright © 2008, Elsevier, Inc. All rights reserved.

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530 proteolytic release of the core from the CUB domain is required for the activation of PDGF C and PDGF D, although activity for the full-length peptide and independent activity for the CUB domain have been postulated [3, 5, 6]. PDGFs must form homo- or heterodimers to exhibit activity, and they can form PDGF AA, BB, AB, CC, or DD dimers [3]. The various pdgf genes are conspicuously expressed during development and in adult tissues. Transcripts for the pdgf a, pdgf b, and pdgf c genes are detected in osteoblasts, but their basal expression is relatively low [3, 7, 8, 9]. PDGF D is synthesized by myocardial and vascular cells, where it induces cell proliferation and fibrosis, but there are no reports of PDGF D synthesis by the osteoblast [10]. Since PDGF is present in circulating platelets, it can act as a local and systemic regulator of cell function [11]. The five PDGF isoforms described can interact with either one of two PDGF receptors, which have differential binding specificity for the various PDGF dimers [12, 13, 14, 15]. PDGF receptor (PDGFR) α ligates PDGF A, B, and C chains and PDGFR β binds PDGF B and D chains [3]. The two PDGF receptors are structurally and functionally related, and PDGF binding results in receptor dimerization and the formation of PDGF αα, ββ, and αβ receptor dimers [3]. For receptor activation, PDGF AA and PDGF CC require PDGFR αα, or αβ dimers, PDGF DD requires PDGFR ββ, or αβ dimers, whereas PDGF AB and PDGF BB can activate either PDGFR αα, αβ, or ββ dimers. PDGF AA, AB, and BB are the isoforms studied more extensively in skeletal cells, and they exert similar biological actions. However, in skeletal as well as nonskeletal cells, PDGF BB is more potent than PDGF AA, and PDGF AB has intermediate activity [16]. The primary action of PDGF in bone is the stimulation of DNA synthesis and of cell replication. Histomorphometric analysis reveals an increase in cells of the osteoblastic lineage, but the effect is not specific and PDGF causes a generalized stimulation of cell replication in bone [17]. The mitogenic effect is observed primarily in the periosteal layer, a zone rich in fibroblasts and preosteoblasts. It could be presumed that preosteoblastic cells, replicating under the influence of PDGF, eventually differentiate into mature osteoblasts. However, an inhibitory effect on the differentiation of stromal cells into cells of the osteoblastic lineage has been reported [18]. This would indicate that the cells affected could remain in a proliferative undifferentiated state. Some cells, responding to other local signals, may differentiate, and as a consequence of the increased cell number, a modest increase in collagen synthesis is observed following exposure to PDGF. It is important to note that, in accordance with the impaired cell differentiation, PDGF inhibits the expression of the mature osteoblastic

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phenotype, and decreases alkaline phosphatase activity and type I collagen mRNA levels [19, 16, 17]. In calvariae, PDGF inhibits mineral apposition rates. These effects may be direct and indirect since PDGF inhibits the synthesis of IGF-I and -II in osteoblasts, and IGF-I and -II enhance osteoblastic functions [20, 21]. PDGF enhances bone resorption by increasing the number of osteoclasts, an effect that may be secondary to an increase in the expression of interleukin (IL)-6, a cytokine known to induce osteoclastogenesis [22]. In agreement with its effects on bone resorption, PDGF increases the expression of matrix metalloproteinases (MMP) by the osteoblast [23, 24]. PDGF increases the rate of transcription of the collagenase 3 (MMP-13) gene, and mRNA stability in transcriptionally arrested osteoblasts. MMP-13 is a proteinase capable of initiating the degradation of type I collagen at neutral pH, and necessary to achieve a bone resorptive response to parathyroid hormone (PTH) [25]. Cells of the osteoblastic lineage express PDGF α and β receptors. PDGF binding to its osteoblast receptor results in receptor dimerization, and activation of tyrosine kinase activity, leading to activation of protein kinase C (PKC), and intracellular calcium signaling pathways [26, 27]. In rodent, but not in human osteoblasts, IL-1 increases PDGF α receptor transcripts and the binding and mitogenic activity of PDGF AA [16, 28, 29]. TGF β decreases PDGF binding, and hormones have no effect on PDGF binding to osteoblasts [30]. Information on the activity of PDGF CC and PDGF DD in skeletal cells is limited. PDGF CC interacts with PDGF αα and αβ receptor dimers, and has potent mitogenic activity for mesenchymal cells [4]. PGDF CC induces the differentiation and regulation of endothelial cells and has potent angiogenic properties, directly or indirectly by upregulating VEGF [31]. These properties of PDGF CC could be important during the vascularization of endochondral bone formation, as it has been described for VEGF. PDGF DD interacts with PDGF β receptors, has mitogenic activity for vascular cells, and induces tissue fibrosis, but its effects on the skeleton are not known [10]. Although there is considerable knowledge about the actions of PDGF in vitro, information about its effects on the skeleton in vivo is more limited. Consistent with some of its in vitro effects, the systemic administration of PDGF BB to ovariectomized rats prevents bone loss, and increases the number of osteoblasts and bone formation [32]. It is likely that the mitogenic effects of PDGF on preosteoblasts result in an increased number of osteoblasts, which are capable of forming bone. PDGF does not change osteoclast number when administered systemically to ovariectomized rats, but this may be related to this particular model

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where the ovariectomy causes a substantial increase in bone resorption and remodeling, precluding an additional effect by PDGF. Topical application of PDGF to craniotomy defects in rodents stimulates soft tissue repair, but not osteogenesis [33]. The effects of PDGF on endothelial cell proliferation and angiogenesis are likely beneficial to the process of wound healing, and PDGF accelerates the healing response of wounds due to an increase in cellularity and in the formation of granulation tissue [34]. Genetically engineered mice with gain and loss of function mutations have provided important information on the physiological role of PDGF during development and post-natality. Null mutations of pdgf b, pdgf a and b receptors cause embryonic lethality, and pdgf a deletions cause prenatal and perinatal death [35]. Therefore, these models have not allowed for the study of the function of PDGF in the postnatal skeleton. pdgf b and pdgf b receptor null mice develop microvascular bleeding and absent vascular and mesangial cells [36, 37]. pdgf a and pdgf a receptor null mutants have defective alveolar formation in the lungs leading to emphysema, and have reduced intestinal villi, thin dermis, and spermatogenic arrest, but pdgf a null mutants do not manifest a skeletal phenotype [38,39]. pdgf c null mice exhibit neonatal lethality and numerous skeletal developmental abnormalities, including cleft palate and spina bifida [40]. Similar defects are observed in pdgf a receptor null mice, which exhibit a phenotype characterized by embryonic lethality, cleft face, spina bifida, and vascular and skeletal defects [38, 39]. Although PDGF B can interact with the PDGF α receptor, loss of function mutations of the pdgf b gene do not resemble the pdgf a receptor null phenotype, indicating that the functions of the PDGF α and β receptors are not redundant [36, 37]. The phenotype of pdgf d gene deletion has not been reported, but overexpression of PDGF DD, like that of PDGF CC, results in tissue fibrosis [41,10]. This may be secondary to the mitogenic properties of PDGF CC and PDGF DD or due to the induction of tissue inhibitors of metalloproteinases. The major source of PDGF is the systemic circulation, and skeletal cells probably become exposed to significant concentrations of PDGF following platelet aggregation. Nevertheless, skeletal cells express the pdgf a, pdgf b and pdgf c genes indicating that PDGF isoforms may act as autocrine regulators of skeletal cell function [8, 42, 9]. The expression of the pdgf a gene is enhanced by TGF β and by PDGF, and that of pdgf b enhanced by TGF β [42, 9]. Following an initial induction of PDGF A, an autoregulatory mechanism may serve to maintain local levels of the growth factor. The regulation of pdgf gene expression in skeletal

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cells is analogous to its regulation in nonskeletal cells indicating that there are no specific transcription factors responsible for the expression of PDGF in bone. Systemic hormones are not known to regulate pdgf gene expression in osteoblasts. Since both TGF β and PDGF are released by platelets following platelet aggregation, the subsequent induction of PDGF by these factors in the bone microenvironment may be a mechanism to ensure adequate levels of PDGF in skeletal tissues in conditions that follow platelet aggregation, such as fracture repair. Under basal conditions there may be no need for skeletal cells to be exposed to significant concentrations of PDGF, and its levels are low [42, 9].

III. VASCULAR ENDOTHELIAL GROWTH FACTOR VEGF shares sequence homology and angiogenic properties with PDGFs, and often they are referred to as members of the PDGF/VEGF family [3, 43]. VEGF A belongs to a gene family also composed of placenta growth factor, vegf b, vegf c, and vegf d [43]. In the mouse, differential splicing results in three VEGF A isoforms, VEGF A 120, VEGF A 164, and VEGF A 188. VEGF A is essential for angiogenesis and vegf a and vegf receptor 1 and 2 genes are expressed by chondrocytes and osteoblasts [44, 45]. VEGF A is required for blood vessel formation and vessel invasion into cartilage during the process of endochondral bone formation, and for chondrocyte survival during skeletal development [46, 47]. The expression of vegf a by chondrocytes requires runt related transcription factor-2 (Runx-2), a transcription factor essential for normal osteogenesis [47]. VEGF A also is required for intramembranous bone formation, it enhances osteoblastic maturation in vitro, and VEGF receptor 1 signaling is essential for osteoclast development [48, 49, 47]. vegf a gene null deletions are lethal due to defective hematopoiesis and defective blood vessel formation, but mice expressing one of three VEGF A isoforms, VEGF A 120, survive and their study has documented the function of VEGF A on endochondral bone formation and osteoblastic maturation [50]. Bone histomorphometric analysis following adenoviral vector delivery of VEGF A also demonstrates a stimulatory effect of VEGF on osteoblast number, and in vivo VEGF A promotes angiogenesis and fracture repair [51, 45]. The expression of VEGF by osteoblasts is regulated by various growth factors. Activation of mitogen activated protein (MAP) kinases by BMP, TGF β, or FGF-2 and activation of phosphatidylinositol-3 (PI3) kinase by IGF-I induces vegf expression in osteoblasts [52, 53, 54, 55]. Following growth factor-induced

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synthesis, VEGF may serve to couple angiogenesis and osteoblastic differentiation and function [56, 46]. The stimulatory effect of IGF-I on vegf a gene expression is mediated by the hypoxia inducible factor (HIF) 2 α. This may result in an increased vascular supply to the local environment, and may serve as a protective mechanism in response to changes in oxygen availability to the osteoblast [52]. It is of interest that the phenotypes of the conditional deletion of hif-1 and of vegf-a in cartilage are analogous [47].

IV.

FIBROBLAST GROWTH FACTOR

FGFs form a family of at least 23 structurally related polypeptides, characterized by their affinity to glycosaminoglycan heparin binding sites [57]. FGFs were initially isolated from the central nervous system and subsequently found in a variety of tissues, where they regulate cell function [58, 59]. Skeletal cells synthesize both FGF-1 and -2, the forms of FGF most extensively studied for their actions on the skeleton [60, 61]. FGF has mitogenic activity in skeletal and nonskeletal cells and potent angiogenic properties [62, 63, 64]. FGF increases a population of cells of the osteoblastic lineage, which differentiate into osteoblasts [63]. However, FGF, like other potent mitogens, does not enhance the differentiated function of the osteoblast directly, and FGF-2 inhibits alkaline phosphatase activity, type I collagen, osteocalcin and osteopontin synthesis, independently of its stimulatory effects on osteoblastic cell growth [65, 66]. These effects are paralleled in vivo and transgenic mice overexpressing FGF-2 are osteopenic, although fgf 2 null mice exhibit impaired bone formation [67, 68]. The inhibitory effect of FGF-2 on osteoblast differentiation is secondary to the induction of the transcription factor Sox 2 and the inhibition of Wnt signaling, which is essential for osteoblastogenesis [69, 70]. Confirming an inhibitory effect on osteoblastic function, FGF-2 suppresses the synthesis of IGF-I, a factor that stimulates the differentiated function of the osteoblast [20]. FGF-2 increases bone resorption by favoring osteoclastogenesis, and stimulates the synthesis of collagenase 3 (MMP-13) by the osteoblast [71, 72]. Marrow stromal cells from fgf-2 null mice exhibit decreased osteoclastogenesis in response to PTH. FGF-2 induces TFG β1 transcription, and TGF β could mediate selected actions of FGF in bone [73]. The actions of FGF can be regulated by modifications in the affinity or number of FGF receptors in target cells. FGF receptors are a family of four distinct receptors, FGFR1 through 4 [74, 75, 76]. FGF receptors are

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transmembrane protein responsive kinases with two to three immunoglobulin-like domains. Differential splicing of the extracellular region of FGF receptors can generate receptor variants with different ligand binding specificity [74, 76]. The four known receptors, and variants, bind the members of the FGF family of polypeptides with different affinity, and have different signaling and mitogenic potential. Activation of FGFR1, 2, and 3 by FGFs induces a mitogenic response, whereas activation of FGFR4 does not [75]. Accordingly, mutations of the fgfr-1, -2, or -3 cause diverse skeletal syndromes including achondroplasia, a common cause of dwarfism [77]. Studies on FGF receptors in preosteoblasts and osteoblasts have been limited. Activation of the signal transducers and activators of transcription 1 regulates FGF receptor in skeletal cells, and suppresses FGFR-3 expression in osteoblasts and mediates FGF-2 actions in chondrocytes [78, 79]. In vivo administration of FGF-2 promotes bone and cartilage repair and topical administration of FGF-2 accelerates fracture healing in rodents and nonhuman primates [80, 81]. The mechanism is related to the mitogenic properties of FGF-2 in skeletal cells in conjunction with its angiogenic activity. Although studies in fgf-2 null mice demonstrate that FGF-2 is required for bone formation, transgenic mice overexpressing FGF-2 in the bone environment are osteopenic [68, 67]. This observation is in accordance with in vitro studies demonstrating an inhibitory effect of FGF-2 on Wnt signaling, IGF-I expression, and osteoblastic function [20, 70]. Embryos harboring null mutations of the fgf receptor 2 die prior to skeletogenesis, but conditional inactivation of the FGF receptor 2 results in skeletal dwarfism secondary to decreased proliferation of osteoprogenitors without affecting osteoblast differentiation [82]. These observations confirm early in vitro studies demonstrating a central role of FGF-2 on preosteoblastic cell proliferation, but not a stimulatory effect on osteoblastic function. Investigations on the regulation of FGF synthesis in skeletal cells are limited to FGF-2. In fibroblasts, heat shock induces the release of FGF, suggesting that its secretion is related to cellular stress [83]. The regulation of FGF-2 expression in osteoblasts and nonskeletal fibroblasts is similar, and TGF β1 and FGF-2 increase FGF-2 synthesis in osteoblasts [61]. Sequence analysis of the FGF-2 promoter reveals AP-1 recognition sequences; therefore, signals that induce Fos and Jun, components of the AP-1 complex, have the potential to upregulate fgf-2 gene transcription [84]. PDGF enhances the expression of FGF-2 mRNA levels in fibroblasts, and possibly in osteoblasts. Therefore, skeletal growth factors with mitogenic properties, such as FGF-2 and PDGF, are major inducers of FGF-2 synthesis. PTH

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Chapter 19 Skeletal Growth Factors

causes a transient induction of FGF-2 transcripts in osteoblasts [85]. FGF is stored in the extracellular matrix, where it is complexed by extracellular matrix and cell surface-associated heparan sulfate proteoglycans, which may prolong its half-life and allow future interactions with its receptors [86]. Binding of FGF to heparan sulfate proteoglycans is a necessary step for the presentation of the factor to its receptor. The heparan sulfate proteoglycan syndecan is an integral membrane proteoglycan that binds FGF and components of the extracellular matrix, suggesting that it can regulate the effects of FGF-2 on cell growth [57].

V. TRANSFORMING GROWTH FACTOR BETA TGF β belongs to a family of closely related polypeptides with various degrees of structural homology and important effects on cell function [87, 88]. There are five TFG β genes, and mammalian cells express TGF β1, 2, and 3. Bone matrix contains TGF β1, 2, and 3 homodimers as well as 1.2 and 2.3 heterodimers [88, 89]. TGF β1, 2, and 3 have similar effects on bone cell function although their potency differs [89]. TGF β stimulates DNA synthesis and cell replication and has a modest stimulatory effect on collagen synthesis in calvariae [90]. Bone histomorphometric analysis of intact rat calvariae exposed to TGF β demonstrates a stimulatory effect on mineral apposition rates, and in vivo studies have confirmed a stimulatory effect of TGF β on bone formation [91, 92, 93]. The effects of TGF β on cell replication and the differentiated function of the osteoblast are dependent on the target cell, its state of differentiation and the culture conditions used. In primary cultures of rat osteoblasts, TGF β has a biphasic stimulatory effect on DNA synthesis, whereas in rat osteosarcoma cells it inhibits cell growth [94, 95, 96]. In osteoblasts, TGF β inhibits alkaline phosphatase activity and osteocalcin synthesis, suggesting an inhibitory effect on their differentiated function. TGF β stimulates collagen synthesis by increasing type I collagen gene transcription [97]. In osteosarcoma cells, TGF β increases type I collagen, fibronectin, osteonectin, and osteopontin mRNA expression [98]. In stromal cell cultures, TGF β favors chondrocytic differentiation, and opposes the effect of BMP on osteoblastogenesis [99]. Consequently, whereas TGF β stimulates selected parameters of osteoblastic function, it does not direct the maturation of undifferentiated cells toward osteoblasts, and seems more relevant to chondrogenesis than to osteoblastogenesis. The actions of TGF β on bone resorption also have been a source of controversy. TGF β has a biphasic effect on osteoclastogenesis.

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533 At low concentrations it enhances osteoclast formation, whereas at high concentrations it is inhibitory. The stimulatory effect on osteoclast formation seems to be related to the production of prostaglandins, and the inhibitory effect secondary to a decrease in the differentiation of early stem cells into cells of the osteoclast lineage because of a shift toward cells of the granulocyte lineage [100, 101]. The impaired osteoclastogenesis would explain a decrease in bone resorption [102]. Osteoblasts express type I and II TGF β receptors, and PTH and glucocorticoids modify TGF β binding to its receptors on osteoblasts [103, 104]. Glucocorticoids shift the binding of TGF β from type I and II receptors to betaglycan, which is not a signal transducing molecule [105]. In accordance with its actions in vitro, the systemic administration of TGF β2 to experimental animals stimulates cancellous bone formation, and subperiosteal injections of TGF β1 and 2 induce osteogenesis and chondrogenesis in rat femurs [106, 93]. In contrast, transgenic mice overexpressing TGF β2, under the control of the osteoblast specific osteocalcin promoter, exhibit osteopenia [107]. Although TGF β induces chondrocyte differentiation, suppression of TGF β signaling in vivo also favors terminal chondrocyte differentiation, suggesting a dual role of TGF β on chondrocyte maturation [108]. Targeted gene disruption of the mouse tgf b gene does not result in changes in skeletal development [109]. This may be secondary to an early lethal phenotype of tgf b null mice, due to a severe inflammatory disease. TGF β enhances soft tissue wound healing, and like FGF-2 it may play a role in fracture repair [110]. However, its cytostatic actions and its fibrosis-inducing properties would limit its topical and systemic use in the treatment of metabolic bone disorders [111, 112, 113]. TGF β is secreted as a latent high molecular weight complex consisting of the carboxy terminal remnant of the TGF β precursor and a TGF β binding protein [114, 115, 116, 117]. The biologically active levels of TGF β depend on changes in its synthesis and in the activation of its latent form. By inducing lysosomal proteases, bone regulatory agents increase the levels of biologically active TGF β in bone [118, 119]. FGF, TGF β itself, and estrogens increase TGF β1 synthesis in osteoblasts, and ovariectomy reduces the concentration of TGF β in rodent bone [118, 120]. The latter may suggest a role of TGF β in the abnormalities observed in the estrogen deficient state. There have been limited studies on the regulation of TGF β2 and TGF β3 synthesis in osteoblasts, but the tgf b2 and tgf b3 gene promoters contain cyclic AMP responsive elements, indicating a potential regulation by cyclic AMP inducers [121, 122].

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BONE MORPHOGENETIC PROTEIN

BMPs are members of the TGF β superfamily of polypeptides, and were originally identified because of their ability to induce endochondral bone formation [123, 124, 125]. BMPs account for most of the TGF β superfamily of peptides, and the proteins display extensive conservation among species [123]. BMP-1 is a protease, which cleaves procollagen fibrils, and is unrelated to other BMPs [126]. BMP-3, or osteogenin, is different from other BMPs since it lacks their osteogenetic properties, and it inhibits osteogenesis and opposes BMP-2 actions [127, 128, 129]. Although BMPs are synthesized by skeletal cells, their synthesis is not limited to bone, and they are expressed by a variety of extraskeletal tissues, where they play a critical role in developmental and cellular functions. BMP-1 through -6 are expressed by osteoblasts, but the degree of expression depends on the cell line examined, and its stage of differentiation [130, 131, 132, 133]. BMP-2, -4, and -6 are the most readily detectable BMPs in osteoblast cultures and BMP-2 and -4 are 92% identical in their amino acid sequence and have virtually identical biological activities. Experiments using kinase-deficient truncated BMP receptors or using BMP antagonists have demonstrated that the locally synthesized BMPs play an autocrine role in osteoblastic differentiation and function [134]. A fundamental function of BMPs is the induction of mesenchymal cell differentiation toward cells of the osteoblastic lineage, and to the promotion of osteoblastic activity [135, 136]. As osteoblasts undergo terminal differentiation, they undergo apoptosis, an expected result of cell maturation [137,138,139]. Consequently, BMPs favor osteoblastic cell death. The genesis and differentiation of bone-forming osteoblasts and boneresorbing osteoclasts are coordinated events. Receptor activator of nuclear factor-κ B-ligand (RANK-L) and colony stimulating factor 1 are osteoblast products and are major determinants of osteoclastogenesis [140]. Osteoprotegerin, a secreted receptor of the tumor necrosis factor receptor family, acts as a decoy receptor that binds RANK-L, precluding RANK-L binding to RANK and its effects on osteoclastogenesis and bone resorption. BMPs play a direct and indirect role in osteoclastogenesis. By inducing osteoblast maturation, there is increased RANK-L availability. In addition, BMPs sensitize osteoclasts to the effects of RANK-L on osteoclastogenesis and osteoclast survival [141, 142]. BMPs also induce osteoprotegerin transcription, and this may temper their effects on osteoclastogenesis [143]. BMPs inhibit collagenase 3 or MMP-13 expression in osteoblasts, a matrix metalloprotease required for normal bone resorption [144, 145].

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BMPs induce endochondral ossification and chondrogenesis [146]. BMPs stimulate chondrocyte maturation and function, increasing the expression of type II and type X collagens and the incorporation of sulfate into glycosaminoglycans [147,148]. Overexpression of BMP-2 and -4 in developing limbs results in an increase in chondrocyte number and in matrix cartilage, which may lead to joint fusions [149]. The anabolic effects of Indian and Sonic hedgehog and BMP-2 and -4 in metatarsal cultures are analogous, and BMPs mediate their actions on endochondral ossification [150]. Whereas BMPs induce osteogenesis and chondrogenesis, they prevent terminal differentiation of myogenic cells, inhibiting the transcription of the muscle-specific nuclear factors MyoD and myogenin [151, 152]. BMPs act in conjunction with other growth factors, and by inducing the differentiation of cells of the osteoblastic lineage, BMPs increase the pool of IGF-I producing and IGF-I target cells [153]. BMPs interact with type IA or activin receptor like kinase (ALK)-3 and type IB or ALK-6, and BMP type II receptors [154]. Upon ligand binding and activation of the type I receptor, dimers of the type I and type II receptor initiate a signal transduction cascade activating the signaling mothers against decapentaplegic (Smad) or the MAP kinase signaling pathways [155, 156]. Following receptor activation by BMPs, Smad 1, 5 and 8 are phosphorylated at serine residues, and translocated into the nucleus following heterodimerization with Smad 4 [157, 158]. In the nucleus, Smads can bind to DNA sequences directly, bind and cooperate with other transcription factors, or bind and displace nuclear factors from their DNA binding sites. MAP kinase signaling results in P38 MAP kinase or extracellular regulated kinase (ERK) activation by BMPs [87, 159]. The transcriptional and post-transcriptional regulation of BMP expression in osteoblasts reveals autoregulation of BMP synthesis since BMP-2 and -4 mRNA levels are BMP dependent [130, 132]. BMPs cause an early, short lived, induction of BMP-4 mRNA in osteoblasts followed by an inhibitory effect. A positive feedback loop regulating BMP-2 and -4 expression involving Runx-2 is possible since BMPs induce Runx-2 expression and the BMP-2 and -4 promoters contain Runx-2 binding sequences. BMP-6 expression in osteoblasts is steroid-dependent, and BMP-6 mRNA levels are induced by estrogens [133]. Mice deficient in BMP-2 are not viable due to placental and developmental defects, and the bmp-4 null mutation is lethal between 6.5 and 9.5 days of gestation due to a lack of mesodermal differentiation, and patterning defects [160, 161]. Mice with disruptions of the BMP signaling smad 5 gene also develop multiple embryonic defects, some reminiscent of those observed

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Chapter 19 Skeletal Growth Factors

in bmp-2 null mutants [162, 163]. The lethality of these mutations has prevented the assessment of the impact of BMP-2 and -4 on the adult skeleton. The bmp-6 null mutation is not lethal, and skeletogenesis is normal except for delayed ossification in the sternum [164]. bmp gene inactivation results in significant developmental defects outside the skeleton, and bmp-7 null mice display lack of eye and glomerular development, and bmp-8 null mutations result in defective spermatogenesis [165, 166]. BMP activity is regulated by a large group of secreted polypeptides that bind and limit BMP action. These extracellular BMP antagonists prevent BMP signaling by binding BMPs, and precluding their binding to cell surface receptors [167,168]. Extracellular BMP antagonists include noggin, follistatin and follistatin related gene; ventroptin; twisted gastrulation; the chordin family, which is comprised of chordin, chordin-like, neuralin, CR rich motor neuron, BMP binding endothelial cell precursor-derived regulator, kielin, and crossveinless; and the Dan/cerberus family of genes, which is comprised of the tumor suppressor Dan, Cerberus, Cer 1, gremlin, and its rat homologue drm, the protein related to Dan and Cerberus, caronte, Dante, sclerostin (the product of the sost gene), Wise, and Coco [167, 169, 170, 171]. It is of interest that selected BMP antagonists, such as sclerostin and Coco, also block Wnt signaling [172, 173]. The pattern of tissue expression of BMP antagonists is dependent on the gene studied. Sclerostin is expressed selectively in osteoblasts and osteocytes, where it is regulated by PTH, and ectodin is expressed in tooth enamel [174, 175]. Overexpression of noggin and gremlin, two classic BMP antagonists, or sclerostin, in the skeletal microenvironment prevents osteoblastic differentiation in vitro, and in vivo causes osteopenia secondary to decreased bone formation [176, 177, 178, 179]. Inactivation of the noggin gene causes intrauterine lethality, and articular developmental defects leading to joint fusions [180]. It is of interest that the synthesis of many BMP antagonists, such as that of noggin and gremlin, is induced by BMPs in osteoblasts, suggesting the existence of a protective mechanism to prevent skeletal cells from excessive exposure to BMPs [181, 182].

VII.

INSULIN-LIKE GROWTH FACTOR

IGF-I and -II have structural similarities with proinsulin and are considered essential for normal cell growth in multiple tissues including bone [183]. IGF-I and -II are present in the systemic circulation and are secreted by the osteoblast. In the circulation, IGF-I forms a large molecular weight complex with

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535 insulin-like growth factor binding proteins (IGFBPs) and the acid labile subunit [184]. Although several IGFBPs form the complex, IGFBP-3 is the most abundant, and systemic IGF-I and IGFBP-3 levels are growth hormone (GH) dependent. IGFBPs are present in the circulation at concentrations in excess of those of IGF-I. Consequently, there is little free IGF-I in plasma. Systemic IGF-I is mostly synthesized in the liver and it is responsible for the growth-promoting effects of GH in various tissues [185, 186, 187]. It is important to note that IGF-I is synthesized by multiple peripheral tissues, where it is regulated by alternate hormones, and only to a minor extent by GH. In addition to their function as systemic regulators of growth, IGF-I and -II play an important role in the autocrine and paracrine regulation of cell metabolism in a variety of tissues, including bone [188, 189]. IGF-I and -II are the most prevalent growth factors present in the skeletal tissue. IGF-I and -II have similar effects on bone formation, although IGF-I is more potent than IGF-II [190, 191]. IGFs are modest mitogens, increasing the replication of preosteoblastic cells, which presumably differentiate into mature osteoblasts. The most important function of IGFs is to enhance the differentiated function of the osteoblast. IGFs stimulate type I collagen transcription, an effect independent from their mitogenic actions, and increase mineral apposition rates [192, 191]. IGF-I and -II inhibit collagenase 3 (MMP-13) synthesis by the osteoblast and as a consequence decrease bone collagen degradation [193]. IGF-I and -II are important in the maintenance of the differentiated osteoblast phenotype. IGFs not only enhance osteoblastic function, but their synthesis is differentially regulated by factors that stimulate or inhibit the differentiated expression of the osteoblastic phenotype [20]. A similar role has been suggested for IGF-II in myoblasts, where its expression follows that of genes that are determinants of myogenic differentiation [194]. It is important to note that whereas IGF-I stimulates the differentiated function of the osteoblast, it does not induce the differentiation of marrow stromal cells toward the osteoblastic pathway [195]. Indirectly, IGF-I might favor osteoblastogenesis since it stabilizes β catenin; consequently it has the potential to enhance the Wnt/β catenin signaling pathway, which is essential for osteoblastogenesis [196]. Although the primary role of IGFs is the stimulation of bone formation, IGF-I can increase the synthesis of RANK-L by osteoblasts and, in this way, enhance osteoclast recruitment, although in vivo experiments have demonstrated an inconsistent impact of IGF-I on osteoclastogenesis [197, 198, 199]. Skeletal cells express the IGF-I and IGF-II receptors, and the IGF-I receptor mediates their anabolic actions. This receptor is a transmembrane glycoprotein

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536 tetramer with ligand-activated tyrosine kinase activity. Insulin receptor substrate (IRS) 1 and 2 are well-characterized substrates for the IGF receptor tyrosine kinase, mediating the effects of IGF-I [200, 201]. In osteoblasts, tyrosine phosphorylation of IRS molecules by the activated receptor results in the activation of PI-3 kinase-phospho Akt signaling or in the activation of the MAP kinases, p38, Jun-N-terminal kinases and ERK1/2 [202]. The IGF-II receptor is the same as the mannose-6-phosphate receptor, does not have a function in IGF signal transduction, and clears IGF-II, regulating its levels during fetal development [203]. IGF-I receptor number in osteoblasts can be modulated by various agents, known to regulate bone cell metabolism, including PDGF, glucocorticoids, and 1,25 dihydroxyvitamin D3 [204, 205, 206, 207]. IGF-I has been tested for its effects on bone metabolism in vivo in experimental animals and humans. IGF-I increases bone formation and prevents trabecular bone loss in experimental conditions of skeletal unloading and increases bone mineral density (BMD) in ovariectomized animals [208]. The short-term administration of IGF-I to normal humans results in an increase in serum levels of type I procollagen peptide and an increase in the excretion of collagen crosslinks, demonstrating an increase in bone turnover [209]. IGF-I increases BMD in patients with osteopenia secondary to anorexia nervosa, but the potential use of IGF-I in humans may be limited by possible side effects and the lack of skeletal specificity [210]. The content of IGF-I in human cortical bone decreases with age, a decline that parallels the one observed in serum concentrations of IGF-I with aging [211,212]. Consequently, it is not known whether it is due to a decrease in skeletal IGF-I accumulation from the systemic circulation, or due to a decrease in the synthesis of IGF-I by the aging skeleton. The study of genetically engineered mice has provided additional insight into the action of IGF-I in vivo. Transgenic mice overexpressing IGF-I under the control of the osteocalcin promoter exhibit a transient increase in trabecular bone volume secondary to an increase in osteoblast function and bone formation [197]. igf-1 and igf-1 receptor gene deletions have provided valuable information on the role of IGF-I during development, and conditional gene deletions have provided information on the effects of IGF-I in the adult skeleton [213, 186]. igf-1 deletion causes a reduction in chondrocyte maturation, and femoral length, and osteopenia secondary to a decrease in bone formation [186, 214]. Mice carrying mutations of the GH releasing hormone receptor or of the GH receptor have absent GH secretion or action, and consequently low serum IGF-I [215, 216]. These models allow for the determination of the contribution of systemic IGF-I

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to the skeleton, and the phenotype of either mutant is characterized by small growth plates, osteopenia and reduced cortical bone, but normal trabecular bone volume. This suggests a more pronounced role of systemic IGF-I on cortical than on trabecular bone. Mice carrying a liver-specific igf-1 deletion display a 75% reduction in total serum IGF-I levels, normal free IGFI levels, and absent skeletal phenotype attributed to the normal serum levels of free IGF-I and the extra hepatic synthesis of IGF-I [217]. However, mice carrying dual deletions of igf-1 and the acid labile subunit display marked reduction in total serum IGF-I and a significant reduction of cortical bone volume [218]. Igf-1 receptor null mice die after birth and demonstrate severe growth retardation, and the conditional disruption of the igf-1 receptor gene selectively in osteoblastic cells causes a decrease in osteoblast number, and impaired bone formation resulting in reduced trabecular bone volume [186, 198]. This observation documents the fundamental role played by IGF-I in the maintenance of bone formation and structure. Accordingly, deletion of the irs-1 or -2 gene causes osteopenia [219, 220]. However the phenotypes are not identical and irs-1 null mice exhibit low bone turnover osteopenia and do not respond to PTH, whereas igf-2 null mice exhibit increased bone resorption and respond to the anabolic effects of PTH in bone [220]. The various models described confirm the anabolic function of IGF-I on bone. Skeletal IGF-I might play a more important role in the maintenance of trabecular bone, and systemic IGF-I might be more important in the regulation of cortical bone. The igf-1 gene is complex, contains six exons, and has alternate promoters in exons 1 and 2 [221, 222]. The exon 1 promoter has four transcription initiation sites, and is responsible for the regulation of IGF-I expression in most extrahepatic tissues including bone [223]. The IGF-I exon 2 promoter has two transcription initiation sites and is responsible for the transcriptional regulation of IGF-I by GH in the liver [223]. IGF-I exon 2 is minimally expressed by osteoblasts, and GH is not a major inducer of IGF-I in these cells [224]. Hormones and growth factors regulate the synthesis of IGF-I in osteoblasts, and PTH, PTH related peptide, and other inducers of cyclic AMP in osteoblasts increase IGF-I synthesis [224]. IGF-I mediates selected anabolic actions of PTH in bone in vitro and in vivo [225]. The stimulatory effect of PTH on collagen synthesis in vitro is decreased by IGF-I neutralizing antibodies, and the stimulatory effect of PTH on bone formation in vivo is not observed in igf-1 or irs-1 null mice [226, 220]. These observations do not exclude the possibility that other factors mediate selected actions of PTH on the skeleton. For example, the effects of PTH on cell replication in the skeleton are independent

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Chapter 19 Skeletal Growth Factors

of IGF-I synthesis and are dependent on Notch activation [227]. PTH also increases the levels of, and activates, skeletal TGF β, which could mediate selected effects of PTH in bone [228]. Estrogens increase and glucocorticoids inhibit IGF-I synthesis in osteoblasts [229, 230]. Selected inhibitory effects of glucocorticoids on bone metabolism can be explained by reduced IGF-I levels in the bone microenvironment. However, glucocorticoids also inhibit osteoblastic gene expression and function directly. In addition to hormones, skeletal growth factors regulate IGF-I synthesis. PDGF, FGF, and TGF β1 decrease IGF-I transcripts and polypeptide levels in osteoblasts, and this inhibition of IGF-I synthesis correlates with their inhibitory actions on osteoblastic differentiated function [20]. In contrast, BMP-2, an agent that enhances osteoblastic differentiation and function, increases IGF-I synthesis in osteoblasts [153]. The igf-2 gene is complex and contains four promoters, and in osteoblasts, like in hepatocytes, IGF-II expression is under the control of the IGF-II P3 promoter [231, 232]. Hormones do not modify IGF-II synthesis in skeletal cells. The skeletal growth factors FGF-2, PDGF, and TGF β1 inhibit IGF-II transcription by inhibiting IGF-II P3 activity, an effect analogous to their inhibition of IGF-I expression, demonstrating a coordinated suppression of IGF-I and -II synthesis by mitogenic growth factors [231].

VIII. INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS IGFBPs are a family of related proteins known to bind specifically IGF-I and -II. There are six classic IGFBPs, termed IGFBP-1 to -6, and additional IGFBP related proteins [184]. There are significant structural similarities in IGFBPs among species, indicating a high degree of evolutionary conservation. Osteoblasts express IGFBP-1 to -6 transcripts [233]. IGFBPs regulate the bioavailability of IGFs and prevent their degradation. IGFBPs can potentiate or inhibit the effects of IGF-I and -II on cell function and vary in their affinity for IGF-I and IGF-II [184, 183]. The binding of IGFs to IGFBPs may sequester the growth factor and preclude its interactions with cell surface receptors, although IGFBPs associated with the extracellular matrix may increase the local effective concentration of the growth factor and potentiate its effects [234, 235]. In addition, IGFBPs may have IGF independent effects and regulate cellular events directly. IGFBP-2 is important in the storage and transport of IGFs, and IGFBP-2 serum levels correlate with BMD in humans [236]. In vitro, IGFBP-2 prevents the effects

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537 of IGF-I on osteoblast function, and overexpression of IGFBP-2 under the control of the cytomegalovirus (CMV) promoter leads to small mice with decreased bone mineral content and failure to respond to the anabolic effects of GH in bone [237]. IGFBP-3 is the major component of the IGF complex in serum and, like the circulating IGF-I, is GH dependent [184]. IGFBP-3 can inhibit or stimulate IGF activities, the latter by upregulating IGF-I delivery to cell surface receptors. Overexpression of IGFBP-3 under the control of the CMV or phosphoglycerate kinase promoter causes growth retardation and osteopenia [238]. IGBP4 is an IGF-I inhibitory binding protein, but under specific conditions IGFBP-4 and IGFBP-5 were reported to stimulate bone cell function independent from their interactions with IGF-I [239, 240]. However, transgenic mice overexpressing either IGFBP-4 or IGFBP-5 under the control of the osteoblast specific osteocalcin promoter exhibit osteopenia and decreased bone formation [241, 242]. The osteopenia is probably secondary to sequestration of the IGF-I present in the bone microenvironment inhibiting its biological activity. It is possible that the different reported effects of IGFBP-4 and -5 are dependent on their interactions with extracellular matrix proteins, or on the levels of IGFBP present in a specific tissue. However, both transgenic models indicate that IGFBP-4 and IGFBP-5 are inhibitory proteins in the skeletal environment. This was documented further using retroviral vectors to overexpress IGFBP-5, in osteoblastic cells, which provoked an inhibition of osteoblastic cell function [243]. IGFBP-1 is important for glucose homeostasis, and there is limited information on the function of IGFBP-6 in skeletal tissue. The synthesis of IGFBPs is regulated by transcriptional, post-transcriptional, and post-translational mechanisms. Although the six IGFBPs are expressed by skeletal and nonskeletal cells, their basal and regulated expression is cell specific [244, 245]. In vitro studies indicate that the pattern of IGFBP expression is dependent on the stages of osteoblast differentiation. IGFBP-2 and -5 expression is highest in the proliferative phase of rat osteoblastic cell cultures, and IGFBP3, -4, and -6 expression peaks during the maturation phase [246]. The regulation of IGFBP expression during osteoblastic cell differentiation may be related to the relative levels of autocrine and paracrine factors present in the cellular environment. IGFs increase osteoblast IGFBP-5 expression, whereas growth factors with mitogenic activity inhibit IGFBP-5 and stimulate IGFBP-4 expression [247, 248, 249]. In addition to local autocrine and paracrine factors, systemic hormones modulate IGFBP synthesis; however, the effects appear to be cell line and culture condition dependent [244]. GH increases IGFBP-3 in

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normal rat osteoblasts, but not in osteosarcoma cells, and cyclic AMP inducers increase the synthesis of IGFBP-3, -4, and -5 [245]. Since agents that induce cyclic AMP in osteoblasts also stimulate the synthesis of IGF-I, the induction of the binding proteins may be a mechanism to control overexposure of cells to the newly synthesized IGF-I. Conversely, glucocorticoids inhibit the synthesis of IGF-I, IGFBP-3, -4 and -5, although they increase the expression of the inhibitory IGFBP-2 in osteoblasts, leading to a marked suppression of IGF-I available to skeletal cells [229, 233]. 1,25-dihydroxyvitamin D3 increases osteoblast IGFBP3 and -4 expression [250]. The abundance of IGFBPs in the extracellular space can be regulated by proteolytic degradation. IGFBP proteases have been characterized from diverse sources, including osteoblasts, which secrete MMPs and serine proteases [251]. Interestingly, the protease activity for IGFBP-4, an inhibitory IGFBP, and for IGFBP-5 is modulated by IGFs, which promote the degradation of IGFBP-4 and stabilize IGFBP-5, suggesting an alternate mechanism by which IGF activity can be modulated in bone [252]. The activity or synthesis of IGFBP proteases is modulated by agents known to regulate bone remodeling, such as IL-6 and glucocorticoids [253, 254].

IX.

HEPATOCYTE GROWTH FACTOR

Hepatocyte growth factor (HGF), also known as Scatter factor, is a large molecular weight polypeptide known for its angiogenic and mitogenic properties [255]. HGF plays a role in liver and kidney repair [256, 257]. HGF signals via the product of the protooncogene c-met, a tyrosine kinase-activated receptor, and HGF and c-met are expressed by mesenchymal cells, osteoblasts, and osteoclasts [258, 259]. HGF is mitogenic for cells of the osteoblastic and osteoclastic lineage, and its synthesis by the osteoblast is enhanced by growth factors with a role in wound and fracture repair [260]. Therefore, HGF may play a role in bone remodeling and repair. Studies in transgenic mice overexpressing HGF under the control of the metallothionein I promoter and studies in hgf or c-met null mice have revealed that HGF is required for muscle cell migration [261, 262]. hgf null mutants fail to form normal muscles, but due to embryonic lethality, the skeletal phenotype was not examined. FGF-2 and PDGF increase the synthesis of HGF by osteoblasts, whereas glucocorticoids are inhibitory [258, 262]. Since HGF plays a role in mitogenesis and tissue repair, inhibition of its synthesis by glucocorticoids may be relevant to the inhibitory effect of these steroids on wound healing

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and tissue repair. Recently, HGF and c-met were found to be expressed at the site of fractured bone and HGF to induce BMP receptors [263]. Through this mechanism HGF may contribute to fracture healing and repair.

ACKNOWLEDGMENTS The work described in this chapter was supported by grants from the National Institutes of Health AR 21707, DK 42424, and DK 45227. The author thanks Ms. Marcia Dupont and Ms. Mary Yurczak for valuable secretarial assistance.

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