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Chondrocyte ?-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.

ABSTRACT: OBJECTIVE:To investigate whether ?-catenin signaling in chondrocytes regulates osteoclastogenesis, thereby contributing to postnatal bone growth and bone remodeling. METHODS:Mice with conditional knockout (cKO) or conditional activation (cAct) of chondrocyte-specific ?-catenin were generated. Changes in bone mass, osteoclast numbers, and osteoblast activity were examined. The mechanisms by which ?-catenin signaling in chondrocytes regulates osteoclast formation were determined. RESULTS:The ?-catenin cKO mice developed localized bone loss, whereas cAct mice developed a high bone mass phenotype. Histologic findings suggested that these phenotypes were caused primarily by impaired osteoclast formation, rather than impaired bone formation. Further molecular signaling analyses revealed that ?-catenin signaling controlled this process by regulating the expression of the RANKL and osteoprotegerin (OPG) genes in chondrocytes. Activation of ?-catenin signaling in chondrocytes suppressed Rankl gene transcription through a glucocorticoid receptor-dependent mechanism. The severe bone loss phenotype observed in ?-catenin cKO mice was largely restored by treatment with human recombinant OPG or transgenic overexpression of Opg in chondrocytes. CONCLUSION:?-catenin signaling in chondrocytes plays a key role in postnatal bone growth and bone remodeling through its regulation of osteoclast formation.

SUBMITTER: Wang B

PROVIDER: S-EPMC3932359 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Chondrocyte β-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.

Wang Baoli B Jin Hongting H Zhu Mei M Li Jia J Zhao Lan L Zhang Yejia Y Tang Dezhi D Xiao Guozhi G Xing Lianping L Boyce Brendan F BF Chen Di D

Arthritis & rheumatology (Hoboken, N.J.) 20140101 1

<h4>Objective</h4>To investigate whether β-catenin signaling in chondrocytes regulates osteoclastogenesis, thereby contributing to postnatal bone growth and bone remodeling.<h4>Methods</h4>Mice with conditional knockout (cKO) or conditional activation (cAct) of chondrocyte-specific β-catenin were generated. Changes in bone mass, osteoclast numbers, and osteoblast activity were examined. The mechanisms by which β-catenin signaling in chondrocytes regulates osteoclast formation were determined.<h4 ...[more]

PMID: 24431282

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Project description:The WNT/?-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of ?-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate ?-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for ?-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived ?-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with ?-catenin(fx(exon3)/wt) or ?-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific ?-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific ?-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific ?-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived ?-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.

Dataset Information

Chondrocyte ?-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.

Publications

Chondrocyte β-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.

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