title: CCN1 Regulates Chondrocyte Maturation and Cartilage Development.
abstract: WNT/β-CATENIN signaling is involved in multiple aspects of skeletal development, including chondrocyte differentiation and maturation. Although the functions of β-CATENIN in chondrocytes have been extensively investigated through gain-of-function and loss-of-function mouse models, the precise downstream effectors through which β-CATENIN regulates these processes are not well defined. Here, we report that the matricellular protein, CCN1, is induced by WNT/β-CATENIN signaling in chondrocytes. Specifically, we found that β-CATENIN signaling promotes CCN1 expression in isolated primary sternal chondrocytes and both embryonic and postnatal cartilage. Additionally, we show that, in vitro, CCN1 overexpression promotes chondrocyte maturation, whereas inhibition of endogenous CCN1 function inhibits maturation. To explore the role of CCN1 on cartilage development and homeostasis in vivo, we generated a novel transgenic mouse model for conditional Ccn1 overexpression and show that cartilage-specific CCN1 overexpression leads to chondrodysplasia during development and cartilage degeneration in adult mice. Finally, we demonstrate that CCN1 expression increases in mouse knee joint tissues after meniscal/ligamentous injury (MLI) and in human cartilage after meniscal tear. Collectively, our data suggest that CCN1 is an important regulator of chondrocyte maturation during cartilage development and homeostasis.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.|Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.|Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Tzong-jen
authors.initials: TJ
authors.lastname: Sheu
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.|Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Hoak
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hilton
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.|Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
authors.affiliation: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.|Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Jonason
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002358:Cartilage, Articular / Q000254:growth & development* / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D020219:Chondrogenesis; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D004838:Epiphyses / Q000473:pathology; D000072600:Meniscus / Q000473:pathology; D051379:Mice; D013583:Synovial Membrane / Q000473:pathology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D051176:beta Catenin
keywords: CARTILAGE; CCN1; CHONDROCYTE; β-CATENIN