MOLECULAR MECANISMS OF BONE REMODELLING

MOLECULAR MECANISMS OF BONE REMODELLINGDr. Gabriel Ovidiu Dinu
Floreasca Universitary Emergency Hospital

 

 

 

 

 

 

 

Rezumat

Remodelarea osoasa  este definita ca un proces activ care se bazeaza pe echilibrul perfect intre resorbtia osoasa de catre osteoclasti si formarea osului de catre osteoblasti. Cand echilibrul este dereglat, depunerea masei osoase este compromisa, conducand la numeroase patologii scheletice. De exemplu, pierderea masei osoase si osteoporoza  sunt rezultatul  unei functii crescute a osteoclastilor  asociata  cu o activitate redusa a osteoblastilor. Articolul face trecerea in revista a datelor recente din literatura privind mecanismele moleculare care regleaza functiile celulei osoase, care evidentiaza o relatie complexa intre sistemele imune si scheletice care au in comun numeroase proteine reglatoare precum citokinele, receptorii si factorii de transcriptie. Aceste date deschid o noua cale  pentru identificarea moleculelor tinta  pentru terapiile alternative mai eficiente privind boala osoasa.
Cuvinte-cheie: remodelarea osoasa, osteoblast, osteoclast, osteoporoza, osteopetroza.

 

Abstract
Bone remodelling is defined as an active and dynamic process that relies on the correct balance between bone resorption by osteoclasts and bone deposition by osteoblasts.
When the coupling is lost, the correct bone mass could be compromised, leading to several skeletal pathologies. For example, bone loss and osteoporosis are the result of an increased osteoclast function  associated with a  reduced osteoblast activity. In contrast, other pathologies are related to osteoclast failure to resorbe bone, such as osteopetrosis, a rare genetic disorder characterized by an increased bone mass and also linked to an impairment of bone marrow functions. This review of recent  literature data concerining molecular mechanisms regulatating  bone cell functions which evidenced a complex interplay between the immune and skeletal systems, which share several regulatory molecules including cytokines, receptors and transcription factors. These data  could open new avenue to identify target molecules for alterantive therapies more efficacious against bone diseases.

Keywords: bone remodeling,osteoblast, osteoclast,oseoporosis, osteopetrosis

 

Introduction

Bone is a dynamic tissue caracterised by its reniwal during the life by a process of remodelling which  relies on the correct function of two principal cells of the bone tissue: the osteoclasts, multinucleated cells that destroy the bone matrix, and the osteoblasts, having osteogenic functions. The osteocytes, another important cell type arising from the osteoblasts, are also involved in the remodelling process as they have a mechano-sensorial function[1].
In order to maintain a constant bone mass there is necessary a correct balance between bone resorption and osteogenic functions[1]
There are four phases engaged in bone formation known as:activation phase, resorbtion phase,reverse phase and formation phase.
Activation phase. Different inputs, such as a micro-fracture, an alteration of mechanical loading sensed by the osteocytes or some factors released in the bone microenvironment, including insulin growth factor-I (IGFI), tumour necrosis factor-? (TNF-?), parathyroid hormone (PTH) and interleukin-6 (IL-6), activate the lining cells which are quiescent osteoblasts. As a consequence, lining cells, increase their own surface expression of RANKL (Receptor Activator of Nuclear ?B Ligand), which in turn interacts with its receptor RANK (Receptor Activator of Nuclear ?B), expressed by pre-osteoclasts. RANKL/ RANK interaction triggers pre-osteoclasts fusion and differentiation toward multinucleated osteoclasts.
Resorption phase. Once differentiated, osteoclasts polarize, adhere to the bone surface and begin to dissolve bone. This function requires two steps: i) acidification of the bone matrix to dissolve the inorganic component, and ii) release of lysosomial enzymes, such as cathepins K, and of MMP9, both in charge for the degradation of the organic component of bone. Once accomplished their function, osteoclasts undergo to apoptosis. This is a physiological consequence needed to avoid an excessive bone resorption.
Reverse phase. The reverse cells, whose role has not been yet completely clarified, perform this phase. Indeed, it is known that they are macrophage-like cells with a likely function of removal of debris produced during matrix degradation.
Formation phase. Bone matrix resorption leads to the release of several growth factors herein stored, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs) and transforming growth factor ? (TGF ?), which are likely responsible for the recruitment of the osteoblasts in the reabsorbed area. Once recruited, osteoblasts produce the new bone matrix, initially not calcified (osteoid) and then they promote its mineralization, thus completing the bone remodelling process. Unbalance between the resorption and formation phases mirror an incorrect bone remodelling, which in turn affects the bone mass, eventually leading to a pathological condition.
Osteoblasts arise from mesenchymal stem cells (MSCs), which are pluripotent cells that following a specific program of gene expression may give rise to different tissue specific cells including osteoblasts, chondrocytes, fibroblasts, myocytes and adipocytes [2]
The initial step of osteoblastogenesis is the commitment of MSCs towards an osteo/chondro-progenitor.
A recent report [3] showed that Wnt10b not only shifts the commitment towards an osteo/chondro progenitor, but also inhibits preadipocyte commitment.
This is due to the suppression of the adipogenic transcription factors CCAAT enhancer binding protein ? (C/EBP?) and peroxisome proliferator-activated receptor ? (PPAR?) along with to an induction of transcription factors Runt-related transcription factor 2 (Runx2), distal-less homeobox 5 (Dlx5), and Osterix (Osx), the latter downstream of Runx2 [4].
Conversely, high levels of Wnt signalling with the presence of Runx2 promote osteoblastogenesis at the expense of chondrocyte differentiation [5] Committed pre-osteoblasts are identifiable as they express Alkaline Phosphatase (ALP), one of the earliest markers of osteoblast phenotype. As the pre-osteoblasts cease to proliferate, a key signalling event occurs for development of the large cuboidal differentiated osteoblasts. The active osteoblast is highly enriched in ALP and secrete bone matrix proteins such as collagen I and several non-collagenous proteins including osteocalcin, osteopontin, osteonectin and bone sialoprotein II (BSPII). As a rule, ALP and the type 1 parathyroid receptor (PTH1R) are early markers of osteoblast progenitors that increase as osteoblasts mature and deposit matrix, but decline again as osteoblasts become osteocytes, whereas osteocalcin is a late marker that is up-regulated only in post-proliferative mature osteoblasts associated with mineralized osteoid [6].

 

Principal mechanisms of osteoblast regulation


Runt-related transcription factor 2 (Runx2). This transcription factor plays a key role in skeletal development as it is a master gene for osteoblast differentiation, driving the early steps of mesenchymal commitment toward the pre-osteoblast phenotype [7]. Indeed, in Runx2 null mice lack of osteoblast differentiation results in the absence of bone formation, and chondrocytes of cartilages templates fail to undergo hypertrophy, while overexpression of a dominant-negative form of Runx2 in osteoblasts inhibits bone formation [8].
Interestingly, Runx2 overexpression also leads to osteopenia, thus indicating that this factor at inappropriately high levels can inhibit the process of osteoblast maturation [9]. In humans, haploinsufficiency of Runx2 causes cleidocranial dysplasia (CCD), an autosomal-dominant disease with abnormalities in bones formed by intramembranous ossification [10].
Among the molecules able to regulate Runx2, BMPs, TGF ?, PTH and FGFs promote its activation, while the transcription factor Twist is a negative regulator [11].
Osterix (Osx). This factor is downstream of Runx2 and, like the latter, is necessary for skeletal formation[12]. To accomplish this function Osx needs to interact with activated NFAT2 (13].
Wnt/?-catenin signalling. Recent reports evidenced a pivotal role of this pathway in bone biology [14] Indeed, the great interest for Wnt signalling in bone field came after the discovery that loss and gain-of-function mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5), a putative Wnt co-receptor, led to the osteoporosis-pseudoglioma syndrome [15] and to high bone mass (HBM) [16] respectively in humans. LRP5 is a transmembrane receptor, which interacts with the frizzled receptor.
Binding of Wnt to frizzled and LRP5/6 receptor complex triggers a signal involving the proteins Disheveled (Dvl), Axin and Frat-1, thus inhibiting the activity of the Glycogen synthase kinase 3? (GSK3?)[17]. This inhibition prevents ?-catenin phosphorylation. Indeed, hypophosporylated ?-catenin is more stable, thus accumulating in the cytoplasm. Upon reaching a certain concentration level, ?-catenin translocates to the nucleus where it interacts with the Tcf/Lef family of transcription factors to regulate the expression of Wnt target genes. In contrast, in the absence of Wnt, GSK3? phosphorylates ?-catenin, thus targeting the protein to proteasome ubiquitination [18].
Wint signalling is subjected to a fine tune regulation by several factors. Among them, the members of the secreted frizzled-related protein (sFRP) family and Wnt inhibitory factor 1 (Wif-1). These molecules are soluble decoy frizzled receptors that prevent interactions between Wnt and frizzled. A second group of inhibitors includes dickkopf (Dkk) and sclerostin (Sost) proteins, which bind to LRP5/6 receptors. Moreover, interaction of the Dkk/LRP complex with kremen internalises the complex for degradation, thus reducing the availability of Wnt receptors [19].
Bone Morphogenetic Proteins (BMPs) Except for BMP-1, all these proteins belong to the TGF-? superfamily. Identification of skeletal abnormalities in animals and patients with mutations in the BMP genes has highlighted the role of these proteins in bone metabolism [20]. In vitro studies demonstrated that treatment with BMPs enhances the expression of ALP, parathyroid hormone related peptide (PTHrP) receptor type I, collagen I and osteocalcin [20] and stimulated the formation of mineralized bone-like nodules [21].

 

REFERENCES

 

1. Nijweide PJ, Burger EH, Klein Nulend J, et al. The osteocyte In: Bilezikian JP, Raisz LG, Rodan GA eds. Principles of bone biology London UK: Academic Press; 1996. 115 126.
2. Grigoriadis AE, Heersche JN, Aubin JE. Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone derived clonal cell population: effect of dexamethasone. J Cell Biol. 1988;106:2139–2151.
3. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt 10b. Proc Natl Acad Sci USA. 2005;102:3324–33295.
4. Gaur T, Lengner CJ, Hovhannisyan H, et al. Canonical WNT signalling promotes osteogenesis by directly stimulating RUNX2 gene expression. J Biol Chem. 2005;280:33132–33140.
5. Glass DA II, Karsenty G. Minireview: In vivo analysis of Wnt signalling in bone. Endocrinology. 2007;148:2630–2634.
6. Nakashima K, de Crombrugghe B. Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet. 2003;19:458–466.
7 Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406.
8. Ducy P, Starbuck M, Priemel M, et al. Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes and Development. 1999;13:1025–1036.
9. Liu W, Toyosawa S, Furuichi T, et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol. 2001;155:157–166.
10. Lee B, Thirunavukkarasu K, Zhou L, et al. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet. 1997;16:307–310.
11. Kaneki H, Guo R, Chen D, et al. TNF promotes RUNX2 degradation through up-regulation of SMURF1 and SMURF2 in osteoblasts. J Biol Chem. 2006;281:4326–4333.]
12. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29.
13. Koga T, Matsui Y, Asagiri M, et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005;11:880–885.
14. Rawadi G, Roman-Roman S. Wnt signalling pathways: a new target for the treatment of osteoporosis. Exp Opin Ther Targets. 2005;9:1063–1077.
15. Gong Y, Slee RB, Fuki N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–523.
16. Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related proteins (LRP5) gene in different conditions with increased bone density. Am J Human Genet. 2003;72:763–771.
17. Clevers H. Wnt/b-catenin signalling in development and disease. Cell. 2006;127:469–480.
18. Baron R, Rawadi G. Minireview: targeting the Wnt/?-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–2643.
19. Mao B, Wu W, Davidson G, et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 2002;417:664–667.
20. Thomas JT, Kilpatrick MW, Lin K, et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet. 1997;17:58–64.
21. Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev. 2000;21:393–411.

 

 

 

 

MOLECULAR MECANISMS  OF BONE REMODELLING

 

 

Dr. Gabriel Ovidiu Dinu

Floreasca Universitary Emergency Hospital

 

Part One

 

Rezumat

Remodelarea osoasa  este definita ca un proces activ care se bazeaza pe echilibrul perfect intre resorbtia osoasa de catre osteoclasti si formarea osului de catre osteoblasti. Cand echilibrul este dereglat, depunerea masei osoase este compromisa, conducand la numeroase patologii scheletice. De exemplu, pierderea masei osoase si osteoporoza  sunt rezultatul  unei functii crescute a osteoclastilor  asociata  cu o activitate redusa a osteoblastilor. Articolul face trecerea in revista a datelor recente din literatura privind mecanismele moleculare care regleaza functiile celulei osoase, care evidentiaza o relatie complexa intre sistemele imune si scheletice care au in comun numeroase proteine reglatoare precum citokinele, receptorii si factorii de transcriptie. Aceste date deschid o noua cale  pentru identificarea moleculelor tinta  pentru terapiile alternative mai eficiente privind boala osoasa.

Cuvinte-cheie: remodelarea osoasa, osteoblast, osteoclast, osteoporoza, osteopetroza.

 

Abstract

Bone remodelling is defined as an active and dynamic process that relies on the correct balance between bone resorption by osteoclasts and bone deposition by osteoblasts.

When the coupling is lost, the correct bone mass could be compromised, leading to several skeletal pathologies. For example, bone loss and osteoporosis are the result of an increased osteoclast function  associated with a  reduced osteoblast activity. In contrast, other pathologies are related to osteoclast failure to resorbe bone, such as osteopetrosis, a rare genetic disorder characterized by an increased bone mass and also linked to an impairment of bone marrow functions. This review of recent  literature data concerining molecular mechanisms regulatating  bone cell functions which evidenced a complex interplay between the immune and skeletal systems, which share several regulatory molecules including cytokines, receptors and transcription factors. These data  could open new avenue to identify target molecules for alterantive therapies more efficacious against bone diseases.

Keywords: bone remodeling,osteoblast, osteoclast,oseoporosis, osteopetrosis

Introduction

Bone is a dynamic tissue caracterised by its reniwal during the life by a process of remodelling which  relies on the correct function of two principal cells of the bone tissue: the osteoclasts, multinucleated cells that destroy the bone matrix, and the osteoblasts, having osteogenic functions. The osteocytes, another important cell type arising from the osteoblasts, are also involved in the remodelling process as they have a mechano-sensorial function[1].

In order to maintain a constant bone mass there is necessary a correct balance between bone resorption and osteogenic functions[1]

There are four phases engaged in bone formation known as:activation phase, resorbtion phase,reverse phase and formation phase.

Activation phase. Different inputs, such as a micro-fracture, an alteration of mechanical loading sensed by the osteocytes or some factors released in the bone microenvironment, including insulin growth factor-I (IGFI), tumour necrosis factor-? (TNF-?), parathyroid hormone (PTH) and interleukin-6 (IL-6), activate the lining cells which are quiescent osteoblasts. As a consequence, lining cells, increase their own surface expression of RANKL (Receptor Activator of Nuclear ?B Ligand), which in turn interacts with its receptor RANK (Receptor Activator of Nuclear ?B), expressed by pre-osteoclasts. RANKL/ RANK interaction triggers pre-osteoclasts fusion and differentiation toward multinucleated osteoclasts.

Resorption phase. Once differentiated, osteoclasts polarize, adhere to the bone surface and begin to dissolve bone. This function requires two steps: i) acidification of the bone matrix to dissolve the inorganic component, and ii) release of lysosomial enzymes, such as cathepins K, and of MMP9, both in charge for the degradation of the organic component of bone. Once accomplished their function, osteoclasts undergo to apoptosis. This is a physiological consequence needed to avoid an excessive bone resorption.

Reverse phase. The reverse cells, whose role has not been yet completely clarified, perform this phase. Indeed, it is known that they are macrophage-like cells with a likely function of removal of debris produced during matrix degradation.

Formation phase. Bone matrix resorption leads to the release of several growth factors herein stored, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs) and transforming growth factor ? (TGF ?), which are likely responsible for the recruitment of the osteoblasts in the reabsorbed area. Once recruited, osteoblasts produce the new bone matrix, initially not calcified (osteoid) and then they promote its mineralization, thus completing the bone remodelling process. Unbalance between the resorption and formation phases mirror an incorrect bone remodelling, which in turn affects the bone mass, eventually leading to a pathological condition.

Osteoblasts arise from mesenchymal stem cells (MSCs), which are pluripotent cells that following a specific program of gene expression may give rise to different tissue specific cells including osteoblasts, chondrocytes, fibroblasts, myocytes and adipocytes [2]

The initial step of osteoblastogenesis is the commitment of MSCs towards an osteo/chondro-progenitor.

A recent report [3] showed that Wnt10b not only shifts the commitment towards an osteo/chondro progenitor, but also inhibits preadipocyte commitment.

This is due to the suppression of the adipogenic transcription factors CCAAT enhancer binding protein ? (C/EBP?) and peroxisome proliferator-activated receptor ? (PPAR?) along with to an induction of transcription factors Runt-related transcription factor 2 (Runx2), distal-less homeobox 5 (Dlx5), and Osterix (Osx), the latter downstream of Runx2 [4].

Conversely, high levels of Wnt signalling with the presence of Runx2 promote osteoblastogenesis at the expense of chondrocyte differentiation [5] Committed pre-osteoblasts are identifiable as they express Alkaline Phosphatase (ALP), one of the earliest markers of osteoblast phenotype. As the pre-osteoblasts cease to proliferate, a key signalling event occurs for development of the large cuboidal differentiated osteoblasts. The active osteoblast is highly enriched in ALP and secrete bone matrix proteins such as collagen I and several non-collagenous proteins including osteocalcin, osteopontin, osteonectin and bone sialoprotein II (BSPII). As a rule, ALP and the type 1 parathyroid receptor (PTH1R) are early markers of osteoblast progenitors that increase as osteoblasts mature and deposit matrix, but decline again as osteoblasts become osteocytes, whereas osteocalcin is a late marker that is up-regulated only in post-proliferative mature osteoblasts associated with mineralized osteoid [6].

Principal mechanisms of osteoblast regulation

Runt-related transcription factor 2 (Runx2). This transcription factor plays a key role in skeletal development as it is a master gene for osteoblast differentiation, driving the early steps of mesenchymal commitment toward the pre-osteoblast phenotype [7]. Indeed, in Runx2 null mice lack of osteoblast differentiation results in the absence of bone formation, and chondrocytes of cartilages templates fail to undergo hypertrophy, while overexpression of a dominant-negative form of Runx2 in osteoblasts inhibits bone formation [8].

Interestingly, Runx2 overexpression also leads to osteopenia, thus indicating that this factor at inappropriately high levels can inhibit the process of osteoblast maturation [9]. In humans, haploinsufficiency of Runx2 causes cleidocranial dysplasia (CCD), an autosomal-dominant disease with abnormalities in bones formed by intramembranous ossification [10].

Among the molecules able to regulate Runx2, BMPs, TGF ?, PTH and FGFs promote its activation, while the transcription factor Twist is a negative regulator [11].

Osterix (Osx). This factor is downstream of Runx2 and, like the latter, is necessary for skeletal formation[12]. To accomplish this function Osx needs to interact with activated NFAT2 (13].

Wnt/?-catenin signalling. Recent reports evidenced a pivotal role of this pathway in bone biology [14] Indeed, the great interest for Wnt signalling in bone field came after the discovery that loss and gain-of-function mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5), a putative Wnt co-receptor, led to the osteoporosis-pseudoglioma syndrome [15] and to high bone mass (HBM) [16] respectively in humans. LRP5 is a transmembrane receptor, which interacts with the frizzled receptor.

Binding of Wnt to frizzled and LRP5/6 receptor complex triggers a signal involving the proteins Disheveled (Dvl), Axin and Frat-1, thus inhibiting the activity of the Glycogen synthase kinase 3? (GSK3?)[17]. This inhibition prevents ?-catenin phosphorylation. Indeed, hypophosporylated ?-catenin is more stable, thus accumulating in the cytoplasm. Upon reaching a certain concentration level, ?-catenin translocates to the nucleus where it interacts with the Tcf/Lef family of transcription factors to regulate the expression of Wnt target genes. In contrast, in the absence of Wnt, GSK3? phosphorylates ?-catenin, thus targeting the protein to proteasome ubiquitination [18].

Wint signalling is subjected to a fine tune regulation by several factors. Among them, the members of the secreted frizzled-related protein (sFRP) family and Wnt inhibitory factor 1 (Wif-1). These molecules are soluble decoy frizzled receptors that prevent interactions between Wnt and frizzled. A second group of inhibitors includes dickkopf (Dkk) and sclerostin (Sost) proteins, which bind to LRP5/6 receptors. Moreover, interaction of the Dkk/LRP complex with kremen internalises the complex for degradation, thus reducing the availability of Wnt receptors [19].

Bone Morphogenetic Proteins (BMPs) Except for BMP-1, all these proteins belong to the TGF-? superfamily. Identification of skeletal abnormalities in animals and patients with mutations in the BMP genes has highlighted the role of these proteins in bone metabolism [20]. In vitro studies demonstrated that treatment with BMPs enhances the expression of ALP, parathyroid hormone related peptide (PTHrP) receptor type I, collagen I and osteocalcin [20] and stimulated the formation of mineralized bone-like nodules [21].

 

REFERENCES

 

1. Nijweide PJ, Burger EH, Klein Nulend J, et al. The osteocyte In: Bilezikian JP, Raisz LG, Rodan GA eds. Principles of bone biology London UK: Academic Press; 1996. 115 126.2.. Grigoriadis AE, Heersche JN, Aubin JE. Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone derived clonal cell population: effect of dexamethasone. J Cell Biol. 1988;106:2139–2151.

3. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt 10b. Proc Natl Acad Sci USA. 2005;102:3324–33295.

4. Gaur T, Lengner CJ, Hovhannisyan H, et al. Canonical WNT signalling promotes osteogenesis by directly stimulating RUNX2 gene expression. J Biol Chem. 2005;280:33132–33140.

5. Glass DA II, Karsenty G. Minireview: In vivo analysis of Wnt signalling in bone. Endocrinology. 2007;148:2630–2634.

6. Nakashima K, de Crombrugghe B. Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet. 2003;19:458–466.

7 Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406.

8. Ducy P, Starbuck M, Priemel M, et al. Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes and Development. 1999;13:1025–1036.

9.. Liu W, Toyosawa S, Furuichi T, et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol. 2001;155:157–166.

10. Lee B, Thirunavukkarasu K, Zhou L, et al. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet. 1997;16:307–310.

11. Kaneki H, Guo R, Chen D, et al. TNF promotes RUNX2 degradation through up-regulation of SMURF1 and SMURF2 in osteoblasts. J Biol Chem. 2006;281:4326–4333.]

12. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29.

13. Koga T, Matsui Y, Asagiri M, et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005;11:880–885.

14. Rawadi G, Roman-Roman S. Wnt signalling pathways: a new target for the treatment of osteoporosis. Exp Opin Ther Targets. 2005;9:1063–1077.

15. Gong Y, Slee RB, Fuki N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–523.

16. Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related proteins (LRP5) gene in different conditions with increased bone density. Am J Human Genet. 2003;72:763–771.

17.. Clevers H. Wnt/b-catenin signalling in development and disease. Cell. 2006;127:469–480.

18.. Baron R, Rawadi G. Minireview: targeting the Wnt/?-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–2643.

19. Mao B, Wu W, Davidson G, et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 2002;417:664–667.

20. Thomas JT, Kilpatrick MW, Lin K, et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet. 1997;17:58–64.

21. Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev. 2000;21:393–411.

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