Physiological loading of joints prevents cartilage degradation through CITED2

Daniel J. Leong, Yong H. Li, Xiang I. Gu, Li Sun, Zuping Zhou, Philip Nasser, Damien M. Laudier, Jameel Iqbal, Robert J. Majeska, Mitchell B. Schaffler, Mary B. Goldring, Luis Cardoso, Mone Zaidi, Hui B. Sun

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)182-191
Number of pages10
JournalFASEB Journal
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Matrix metalloproteinases
  • Mechanotransduction, chondrocyte regulation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    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. (2011). Physiological loading of joints prevents cartilage degradation through CITED2. FASEB Journal, 25(1), 182-191. https://doi.org/10.1096/fj.10-164277