CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear

J Biol Chem. 2003 Nov 21;278(47):47275-80. doi: 10.1074/jbc.M304652200. Epub 2003 Sep 5.


CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is a member of the Cited family of nuclear regulators, previously known as mrg1 (melanocyte-specific gene-related gene 1). CITED2 is inducible by varying stimuli including lipopolysaccharide, hypoxia, and cytokines such as interleukin 9 and interferon gamma. Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes. The C-28/I2 cells were cultured under flow shear at 1-20 dyn/cm2, and the role of CIT-ED2 in regulation of MMPs was examined using the plasmids encoding sense and antisense CITED2 DNA sequences. The results showed that flow shear at 5 dyn/cm2 increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities. Consistent with the coordinated expression patterns of CITED2 and MMPs, overexpression of CITED2 repressed MMP-1 and MMP-13 mRNA levels and activities, whereas antisense CITED2 plasmids prevented the shear-induced down-regulation of MMP expression. Interleukin-1beta induced the formation of p300-Ets-1 complexes without affecting expression of CITED2. Transforming growth factor-beta as well as flow shear at 5 dyn/cm2 stimulated not only the expression of CITED2 but also the association of CIT-ED2 with p300 by dissociating Ets-1 from p300. These results indicate that CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Chondrocytes / metabolism*
  • Collagenases / biosynthesis*
  • Collagenases / genetics
  • DNA-Binding Proteins*
  • Down-Regulation*
  • Humans
  • Matrix Metalloproteinase 1 / biosynthesis*
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 13
  • Nuclear Proteins / metabolism
  • Perfusion
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger / analysis
  • Repressor Proteins*
  • Stress, Mechanical
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / pharmacology


  • CITED2 protein, human
  • DNA-Binding Proteins
  • ETS1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 1