Physiological loading of joints prevents cartilage degradation through CITED2

FASEB J. 2011 Jan;25(1):182-91. doi: 10.1096/fj.10-164277. Epub 2010 Sep 8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cartilage, Articular / metabolism*
  • Cell Line
  • Chondrocytes / metabolism
  • Gene Expression
  • Humans
  • Hydrostatic Pressure
  • Immunohistochemistry
  • Joints / physiology*
  • Male
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism*
  • Mutation
  • Protein Binding
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Restraint, Physical
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Culture Techniques
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • p300-CBP Transcription Factors / metabolism


  • CITED2 protein, human
  • CITED2 protein, rat
  • Ets1 protein, rat
  • Proto-Oncogene Protein c-ets-1
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • p300-CBP Transcription Factors
  • Matrix Metalloproteinase 1