p21 deficiency is susceptible to osteoarthritis through STAT3 phosphorylation

Arthritis Res Ther. 2015 Nov 7;17:314. doi: 10.1186/s13075-015-0828-6.

Abstract

Introduction: Osteoarthritis (OA) is a multifactorial disease, and recent studies have suggested that cell cycle-related proteins play a role in OA pathology. p21 was initially identified as a potent inhibitor of cell cycle progression. However, it has been proposed that p21 is a regulator of transcription factor activity. In this study, we evaluated the role of p21 in response to biomechanical stress.

Methods: Human chondrocytes were treated with p21-specific small interfering RNA (siRNA), and cyclic tensile strain was introduced in the presence or absence of a signal transducer and activator of transcription 3 (STAT3)-specific inhibitor. Further, we developed an in vivo OA model in a p21-knockout background for in vivo experiments.

Results: The expression of matrix metalloproteinase (MMP13) mRNA increased in response to cyclic tensile strain following transfection with p21 siRNA, whereas the expression of aggrecan was decreased. Phospho-STAT3 and MMP-13 protein levels increased following downregulation of p21, and this was reversed by treatment with a STAT3 inhibitor. p21-deficient mice were susceptible to OA, and this was associated with increased STAT3 phosphorylation, elevated MMP-13 expression, and elevation of synovial inflammation. The expression of p21 mRNA was decreased and phosphorylation of STAT3 was elevated in human OA chondrocytes.

Conclusions: The lack of p21 has catabolic effects by regulation of aggrecan and MMP-13 expression through STAT3 phosphorylation in the cartilage tissue. p21 may function as a regulator of transcriptional factors other than the inhibitor of cell cycle progression in the cartilage tissue. Thus, the regulation of p21 may be a therapeutic strategy for the treatment of OA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cartilage, Articular / metabolism
  • Chondrocytes
  • Gene Expression Regulation / physiology*
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoarthritis / metabolism*
  • Phosphorylation
  • Polymerase Chain Reaction
  • RNA, Small Interfering
  • STAT3 Transcription Factor / metabolism*
  • Stress, Mechanical
  • Transfection
  • p21-Activated Kinases / metabolism*

Substances

  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • p21-Activated Kinases