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Physiological loading of joints prevents cartilage degradation through CITED2
Author(s) -
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.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-164277
Subject(s) - cartilage , transactivation , microbiology and biotechnology , matrix metalloproteinase , chemistry , mechanosensitive channels , in vivo , in vitro , chondrogenesis , transcription factor , anatomy , biology , biochemistry , genetics , receptor , ion channel , gene
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 transacti‐vator with ED‐rich tail 2 (CITED2), a mechanosensitive transcriptional coregulator, mediates this chondropro‐tective 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 chondro‐cytes, 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. FASEB J. 25, 182–191 (2011). www.fasebj.org