title: Physiological loading of joints prevents cartilage degradation through CITED2.
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.
authors.affiliation: Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leong
authors.forename: Yong H
authors.initials: YH
authors.lastname: Li
authors.forename: Xiang I
authors.initials: XI
authors.lastname: Gu
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Zuping
authors.initials: Z
authors.lastname: Zhou
authors.forename: Philip
authors.initials: P
authors.lastname: Nasser
authors.forename: Damien M
authors.initials: DM
authors.lastname: Laudier
authors.forename: Jameel
authors.initials: J
authors.lastname: Iqbal
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Majeska
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Schaffler
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.forename: Luis
authors.initials: L
authors.lastname: Cardoso
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.forename: Hui B
authors.initials: HB
authors.lastname: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism*; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006874:Hydrostatic Pressure; D007150:Immunohistochemistry; D007596:Joints / Q000502:physiology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C486381:CITED2 protein, human; C517260:CITED2 protein, rat; C494043:Ets1 protein, rat; D050784:Proto-Oncogene Protein c-ets-1; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D020781:Matrix Metalloproteinase 1
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