Wnt regulation of chondrocyte differentiation

Church, Vicki; Nohno, Tsutomu; Linker, Claudia; Marcelle, Christophe; Francis‐West, Philippa

doi:10.1242/jcs.00152

Cited by 235 publications

(228 citation statements)

References 47 publications

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“…This Wnt is first expressed in cartilage anlagen and expression shifts to perichondrium with further development (16,19). Deletion of the Wnt-5a gene in mice causes a phenotype quite similar to that seen in CA-LEF transgenic mice here (17).…”

Section: Resultsmentioning

confidence: 53%

“…Wnt-3a was found to share similar expression patterns and possibly similar roles (14). Subsequent studies indicated that Wnt-1, -4, and -7a exert inhibitory influences on differentiation of mesenchymal cells into chondrocytes, whereas Wnt-5a and -5b stimulate it (15,16). Wnt-5a and Wnt-5b were also shown to have strong influences on skeletogenesis in chick and mouse embryos (17)(18)(19).…”

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confidence: 99%

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Developmental Regulation of Wnt/β-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification

Tamamura

Otani

Kanatani

et al. 2005

Journal of Biological Chemistry

306

252

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Studies have suggested that continuous Wnt/␤-catenin signaling in nascent cartilaginous skeletal elements blocks chondrocyte hypertrophy and endochondral ossification, whereas signaling starting at later stages stimulates hypertrophy and ossification, indicating that Wnt/␤-catenin roles are developmentally regulated. To test this conclusion further, we created transgenic mice expressing a fusion mutant protein of ␤-catenin and LEF (CA-LEF) in nascent chondrocytes. Transgenic mice had severe skeletal defects, particularly in limbs. Growth plates were totally disorganized, lacked maturing chondrocytes expressing Indian hedgehog and collagen X, and failed to undergo endochondral ossification. Interestingly, the transgenic cartilaginous elements were ill defined, intermingled with surrounding connective and vascular tissues, and even displayed abnormal joints. However, when activated ␤-catenin mutant (⌬-␤-catenin) was expressed in chondrocytes already engaged in maturation such as those present in chick limbs, chondrocyte maturation and bone formation were greatly enhanced. Differential responses to Wnt/␤-catenin signaling were confirmed in cultured chondrocytes. Activation in immature cells blocked maturation and actually de-stabilized their phenotype, as revealed by reduced expression of chondrocyte markers, abnormal cytoarchitecture, and loss of proteoglycan matrix. Activation in mature cells instead stimulated hypertrophy, matrix mineralization, and expression of terminal markers such as metalloprotease (MMP)-13 and vascular endothelial growth factor. Because proteoglycans are crucial for cartilage function, we tested possible mechanisms for matrix loss. ⌬-␤-Catenin expression markedly increased expression of MMP-2, MMP-3, MMP-7, MMP-9, MT3-MMP, and ADAMTS5. In conclusion, Wnt/␤-catenin signaling regulates chondrocyte phenotype, maturation, and function in a developmentally regulated manner, and regulated action by this pathway is critical for growth plate organization, cartilage boundary definition, and endochondral ossification.Skeletogenesis continues to attract much research interest because of its fundamental roles in embryonic development and growth and its susceptibility to pathologies. The process initiates with formation of mesenchymal or ectomesenchymal cell condensations at specific sites and times in the early embryo. As exemplified by the limb, the mesenchymal condensations then undergo chondrogenesis and give rise to cartilaginous long bone anlagen (1, 2). The chondrocytes become organized in growth plates, proliferate, and mature into pre-hypertrophic and hypertrophic chondrocytes. Pre-hypertrophic chondrocytes express genes such as Indian hedgehog, and hypertrophic chondrocytes express a number of characteristic genes, including collagen X, alkaline phosphatase, osteopontin, and metalloprotease (MMP) 1 -13. Eventually, the hypertrophic chondrocytes mineralize their matrix by deposition of apatitic crystals and are replaced by marrow, vascular, and bone cells via an endochondral ossification proce...

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Section: Resultsmentioning

confidence: 53%

mentioning

confidence: 99%

Developmental Regulation of Wnt/β-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification

Tamamura

Otani

Kanatani

et al. 2005

Journal of Biological Chemistry

306

252

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“…Growth factors of the Wnt family are also known to activate Rho GTPases, in addition to other signaling pathways (39,89,90). Several Wnt proteins control chondrocyte proliferation and differentiation (91,92). Among these, Wnt5b has been shown to stimulate chondrocyte proliferation in vivo (73), suggesting that these activities could be mediated by RhoA/ROCK.…”

Section: Discussionmentioning

confidence: 99%

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

Wang

Woods

Sabari

et al. 2004

Journal of Biological Chemistry

118

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Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation. RhoA overexpression in chondrogenic ATDC5 cells results in increased proliferation and a marked delay of hypertrophic differentiation, as shown by decreased induction of alkaline phosphatase activity, mineralization, and expression of the hypertrophic markers collagen X, bone sialoprotein, and matrix metalloproteinase 13. These effects are accompanied by activation of cyclin D1 transcription and repression of the collagen X promoter by RhoA. In contrast, inhibition of Rho/ROCK signaling by the pharmacological inhibitor Y27632 inhibits chondrocyte proliferation and accelerates hypertrophic differentiation. Dominant-negative RhoA also inhibits induction of the cyclin D1 promoter by parathyroid hormone-related peptide. Finally, Y27632 treatment partially rescues the effects of RhoA overexpression. In summary, we identify the RhoA/ROCK signaling pathway as a novel and important regulator of chondrocyte proliferation and differentiation.The development and growth of endochondral bones (such as ribs, vertebrae, and the long bones of vertebrate limbs) are regulated through the highly controlled rates of proliferation and hypertrophic differentiation of growth plate chondrocytes (1-3). In the growth plate, chondrocytes first undergo a series of cell divisions along the longitudinal axis of the growing bone, thereby forming characteristic columns of clonal cells. Chondrocytes then withdraw from the cell cycle and begin to increase their cell volume until reaching the fully differentiated state of hypertrophic chondrocytes. Transition from a proliferating to a hypertrophic phenotype involves numerous changes in gene expression, for example the induction of the collagen X (4, 5), matrix metalloproteinase 13 (6, 7), and bone sialoprotein (BSP) 1 (8 -10) genes. The latter two genes are also expressed by osteoblasts, suggesting similar biological properties of hypertrophic chondrocytes and osteoblasts. The fate of hypertrophic chondrocytes is still debated, but it appears that the majority of these cells undergo apoptosis and are replaced by bone tissue (11). Longitudinal growth of endochondral bones therefore requires both proliferation and differentiation-associated hypertrophy of growth plate chondrocytes.Disruption of chondrocyte proliferation and/or differentiation by gene mutations commonly results in chondrodysplasias that are characterized by skeletal deformities and reduced growth (12)(13)(14). Mutations in genes encoding extracellular matrix molecules, growth factors, receptors, and transcription factors have been identified as causes of several chondrodysplasias. Fo...

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“…A number of signaling pathways have been implicated in the regulation of chondrogenic differentiation and hypertrophy including Sox9, parathyroid hormone-related peptide, Indian hedgehog, bone morphogenetic protein, transforming growth factor-β, and the Wnt signaling pathways [33]. The effects of Wnt signaling on chondrogenesis are complex, as results indicate both stimulation and inhibition of chondrogenesis [34][35][36][37]. This suggests that the regulation by Wnt signaling may depend on the context of the cell or stage of differentiation ( Figure 2).…”

Section: Wnt Signaling In Chondrogenesismentioning

confidence: 99%

Wnt signaling and skeletal development

Liu

Kohlmeier

Wang

2008

Cellular Signalling

138

103

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Wnt proteins are a family of secreted proteins that regulate many aspects of cellular functions. The discovery that mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, could positively and negatively affect bone mass in humans generated an enormous amount of interest in the possible role of the Wnt signaling pathway in skeletal biology. Over the last decade, considerable progress has been made in determining the role of the canonical Wnt signaling pathway in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of non-canonical Wnt signaling in skeletal development. In this review we discuss the current understanding of the role of Wnt signaling in chondrogenesis, osteoblastogenesis, and osteoclastogenesis.

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Wnt regulation of chondrocyte differentiation

Cited by 235 publications

References 47 publications

Developmental Regulation of Wnt/β-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification

Developmental Regulation of Wnt/β-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

Wnt signaling and skeletal development

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