Physiological loading of joints prevents cartilage degradation through CITED2

• Published in: The FASEB journal Vol. 25; no. 1; pp. 182 - 191
• Main Authors: Leong, Daniel J, Li, Yong H, Gu, Xiang I, Sun, Li, Zhou, Zuping, Nasser, Philip, Laudier, Damien M, Iqbal, Jameel, Majeska, Robert J, Schaffler, Mitchell B, Goldring, Mary B, Cardoso, Luis, Zaidi, Mone, Sun, Hui B
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01-01-2011; Federation of American Societies for Experimental Biology
• Subjects: Animals; Blotting, Western; Cartilage, Articular - metabolism; Cell Line; Chondrocytes - metabolism; Gene Expression; Humans; Hydrostatic Pressure; Immunohistochemistry; Joints - physiology; Male; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; matrix metalloproteinases; mechanotransduction, chondrocyte regulation; Mutation; p300-CBP Transcription Factors - metabolism; Protein Binding; Proto-Oncogene Protein c-ets-1 - metabolism; Rats; Rats, Sprague-Dawley; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Communications; Restraint, Physical; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tissue Culture Techniques; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.10-164277

Both overuse and disuse of joints up-regulate matrix metalloproteinases (MMPs) in articular cartilage and cause tissue degradation; however, moderate (physiological) loading maintains cartilage integrity. Here, we test whether CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), a mechanosensitive transcriptional coregulator, mediates this chondroprotective effect of moderate mechanical loading. In vivo, hind-limb immobilization of Sprague-Dawley rats up-regulates MMP-1 and causes rapid, histologically detectable articular cartilage degradation. One hour of daily passive joint motion prevents these changes and up-regulates articular cartilage CITED2. In vitro, moderate (2.5 MPa, 1 Hz) intermittent hydrostatic pressure (IHP) treatment suppresses basal MMP-1 expression and up-regulates CITED2 in human chondrocytes, whereas high IHP (10 MPa) down-regulates CITED2 and increases MMP-1. Competitive binding and transcription assays demonstrate that CITED2 suppresses MMP-1 expression by competing with MMP transactivator, Ets-1 for its coactivator p300. Furthermore, CITED2 up-regulation in vitro requires the p38δ isoform, which is specifically phosphorylated by moderate IHP. Together, these studies identify a novel regulatory pathway involving CITED2 and p38δ, which may be critical for the maintenance of articular cartilage integrity under normal physical activity levels.--Leong, D. J., Li, Y. H., Gu, X. I., Sun, L., Zhou, Z., Nasser, P., Laudier, D. M., Iqbal, J., Majeska, R. J., Schaffler, M. B., Goldring, M. B., Cardoso, L., Zaidi, M., Sun, H. B. Physiological loading of joints prevents cartilage degradation through CITED2.