Physiological loading of joints prevents cartilage degradation through CITED2.
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
Daniel J
DJ
Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029, USA.
Li
Yong H
YH
Gu
Xiang I
XI
Sun
Li
L
Zhou
Zuping
Z
Nasser
Philip
P
Laudier
Damien M
DM
Iqbal
Jameel
J
Majeska
Robert J
RJ
Schaffler
Mitchell B
MB
Goldring
Mary B
MB
Cardoso
Luis
L
Zaidi
Mone
M
Sun
Hui B
HB
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
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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