Comparative Analysis With Collagen Type II Distinguishes Cartilage Oligomeric Matrix Protein as a Primary TGFβ-responsive Gene

Osteoarthritis Cartilage. 2011 Oct;19(10):1246-53. doi: 10.1016/j.joca.2011.07.011. Epub 2011 Jul 29.

Abstract

Objective: This study aims to investigate the regulation of expression of Cartilage oligomeric matrix protein (COMP), which is predominately expressed by chondrocytes and functions to organize the extracellular matrix. Mutations in COMP cause two skeletal dysplasias: pseudoachondroplasia and multiple epiphyseal dysplasia. The mechanism controlling COMP expression during chondrocyte differentiation is still poorly understood.

Design: Primary human bone marrow-derived stem cells were induced to differentiate into chondrocyte by pellet cultures. We then compared the temporal expression of COMP with the well-characterized cartilage-specific Type II collagen (Col2a1), and their response to transforming growth factor (TGF)β and Sox trio (Sox5, 6, and 9) stimulation.

Results: COMP and Col2a1 expression are differentially regulated by three distinct mechanisms. First, upregulation of COMP mRNA precedes Col2a1 by several days during chondrogenesis. Second, COMP expression is independent of high cell density but requires TGF-β1. Induction of COMP mRNA by TGF-β1 is detected within 2h in the absence of protein synthesis and is blocked by specific inhibitors of the TGFβ signaling pathway; and therefore, COMP is a primary TFGβ-response gene. Lastly, while Col2a1 expression is intimately controlled by the Sox trio, overexpression of Sox trio fails to activate the COMP promoter.

Conclusion: COMP and Col2a1 expression are regulated differently during chondrogenesis. COMP is a primary response gene of TGFβ and its fast induction during chondrogenesis suggests that COMP is suitable for rapidly accessing the chondrogenic potential of stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / metabolism
  • Cartilage Oligomeric Matrix Protein
  • Chondrogenesis / physiology*
  • Collagen Type II / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Regulation
  • Glycoproteins / metabolism*
  • Humans
  • Matrilin Proteins
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • SOX9 Transcription Factor / physiology
  • SOXD Transcription Factors / physiology
  • Signal Transduction
  • Transforming Growth Factor beta1 / physiology*
  • Up-Regulation

Substances

  • Cartilage Oligomeric Matrix Protein
  • Collagen Type II
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Matrilin Proteins
  • SOX9 Transcription Factor
  • SOXD Transcription Factors
  • TSP5 protein, human
  • Transforming Growth Factor beta1