Members of the CCN family are key mediators of disease processes. CCN2/CTGF (Connective Tissue Growth Factor) is the major mediator of excess ECM synthesis in all fibrotic conditions studied to date, and CCN1/Cyr61 has potent proangiogenic activities in tumor progression. These proteins are proposed to act as matricellular proteins, coordinating signals mediated by ECM-integrin interactions with other pathways. However, which of the many in vitro activities of these proteins are physiologically relevant is unknown, because their functions in normal tissue development /maintenance are undefined. Studies of targeted mice demonstrate that CCN2/CTGF is essential for chondrogenesis. Whether CCN2 mediates its effects by acting as a ligand for integrins, affecting synthesis of ECM and its modulators, and/or altering the outputs of signaling pathways in cartilage will be investigated in aim one. The consequences of loss of Ccn2 on gene expression in discrete regions of the growth plate will be investigated to test the hypotheses that Ccn2 has global effects on ECM content, and to test whether output of specific signaling pathways is impacted by loss of CCN2. Signaling pathways controlling CCN2 expression in cartilage will be identified in aim two. As Ccn2-l- mice bear a striking resemblance to Sox9 mice, whether CCN2 is a direct target of Sox factors will be investigated. As one of the major phenotypes of Ccn2-/- mice is osteopenia as a result of defective chondrocyte hypertrophy, these studies will also shed light on signaling pathways essential for the ability of hypertrophic cartilage to control subsequent bone formation. A key question regarding the roles of matricellular proteins is the extent to which they fulfill overlapping functions. In vitro studies suggest broadly similar activities for CCNs. However, in no case has it been shown that CCN1 and CCN2 have overlapping functions. A unique role of CCN1 in chondrogenesis and in joint formation is revealed by analysis of Ccn1 null mice.
In aim three this unique joint phenotype is investigated and a Ccn1 floxed allele is used to define the role of CCN1 in cartilage. Analysis of double and compound mutants will test directly the degree to which CCN1 and 2 fulfill overlapping functions. Finally, there is compelling evidence implicating multiple CCN family members as essential for the maintenance of adult articular cartilage. Ccn2 is one of the most abundant transcripts in adult articular cartilage, and articular chondrocytes respond to CCN2, leading to repair of articular defects. In humans, loss of a related gene, CCN6, leads to a progressive pseudorheumatoid dysplasia, a severe form of arthritis, suggesting that a major shared function for CCN proteins is to maintain articular cartilage. We test the hypothesis that CCN2 is vital for the maintenance of adult cartilage using a floxed Ccn2 allele and a tamoxifen-inducible Cre recombinase.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Jiang, Jie; Zhao, Gexin; Lyons, Karen M (2018) Characterization of bone morphology in CCN5/WISP5 knockout mice. J Cell Commun Signal 12:265-270
Zhao, Gexin; Huang, Bau-Lin; Rigueur, Diana et al. (2018) CYR61/CCN1 Regulates Sclerostin Levels and Bone Maintenance. J Bone Miner Res 33:1076-1089
Jiang, J; Leong, N L; Khalique, U et al. (2016) Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis. Haemophilia 22:e527-e536
Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn et al. (2015) WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling. J Biol Chem 290:14004-18
Maeda-Uematsu, Aya; Kubota, Satoshi; Kawaki, Harumi et al. (2014) CCN2 as a novel molecule supporting energy metabolism of chondrocytes. J Cell Biochem 115:854-65
Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan et al. (2014) Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis. Haematologica 99:1149-56
Hall-Glenn, Faith; Aivazi, Armen; Akopyan, Lusi et al. (2013) CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress. J Cell Commun Signal 7:219-30
Tran, Cassie M; Fujita, Nobuyuki; Huang, Bau-Lin et al. (2013) Hypoxia-inducible factor (HIF)-1ýý and CCN2 form a regulatory circuit in hypoxic nucleus pulposus cells: CCN2 suppresses HIF-1ýý level and transcriptional activity. J Biol Chem 288:12654-66
Hall-Glenn, Faith; De Young, R Andrea; Huang, Bau-Lin et al. (2012) CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis. PLoS One 7:e30562
Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei et al. (2011) Connective tissue growth factor is required for normal follicle development and ovulation. Mol Endocrinol 25:1740-59

Showing the most recent 10 out of 22 publications