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Physiological loading of joints prevents cartilage degradation through CITED2.

Authors: Leong, DJ  Li, YH  Gu, XI  Sun, L  Zhou, Z  Nasser, P  Laudier, DM  Iqbal, J  Majeska, RJ  Schaffler, MB  Goldring, MB  Cardoso, L  Zaidi, M  Sun, HB 
Citation: Leong DJ, etal., FASEB J. 2011 Jan;25(1):182-91. Epub 2010 Sep 8.
Pubmed: (View Article at PubMed) PMID:20826544
DOI: Full-text: 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 p38delta isoform, which is specifically phosphorylated by moderate IHP. Together, these studies identify a novel regulatory pathway involving CITED2 and p38delta, which may be critical for the maintenance of articular cartilage integrity under normal physical activity levels.


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RGD Object Information
RGD ID: 5147848
Created: 2011-08-25
Species: All species
Last Modified: 2011-08-25
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.