Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development

• Published in: Journal of bone and mineral research 2012-08, Vol.27 (8), p.1680-1694
• Main Authors: Dao, Debbie Y, Jonason, Jennifer H, Zhang, Yongchun, Hsu, Wei, Chen, Di, Hilton, Matthew J, O'Keefe, Regis J
• Format: Article
• Language: English
• Subjects: Animal models; Animals; beta Catenin - metabolism; Biological and medical sciences; Bone (endochondral); Bone morphogenetic protein 2; Bone Morphogenetic Protein 2 - metabolism; Bone morphogenetic proteins; CARTILAGE; Cartilage - cytology; Cartilage - metabolism; catenin; Cell Differentiation; CHONDROCYTE; Chondrocytes; Chondrocytes - cytology; Chondrocytes - metabolism; Data processing; Embryo, Mammalian - cytology; Fundamental and applied biological sciences. Psychology; Hedgehog protein; Hedgehog Proteins - metabolism; Humerus - cytology; Humerus - embryology; Matrix metalloproteinase; Mice; Ossification; Osteoblastogenesis; Osteoblasts; Osteogenesis; Osteogenesis - physiology; Osteoprogenitor cells; PERICHONDRIUM; Signal Transduction; SKELETAL DEVELOPMENT; Skeleton and joints; Smad Proteins - metabolism; Synergism; Transgenes; vascularization; Vertebrates: osteoarticular system, musculoskeletal system; β-CATENIN
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.1639

The WNT/β‐catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of β‐catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β‐catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β‐catenin in committed growth‐plate chondrocytes has been less robust. To identify the specific role of cartilage‐derived β‐catenin in regulating cartilage and bone development, we studied chondrocyte‐specific gain‐ and loss‐of‐function genetic mouse models using the tamoxifen‐inducible Col2CreERT2 transgene in combination with β‐cateninfx(exon3)/wt or β‐cateninfx/fx floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage‐specific β‐catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)‐mediated mechanism. Second, cartilage‐specific β‐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 β‐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 β‐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. © 2012 American Society for Bone and Mineral Research.