Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis

Arthritis Rheum. 2012 Jan;64(1):141-52. doi: 10.1002/art.33311.

Abstract

Objective: The mechanism responsible for persistent synovial inflammation in rheumatoid arthritis (RA) is unknown. Previously, we demonstrated that expression of the cyclin-dependent kinase inhibitor p21 is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. The present study was undertaken to investigate the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis.

Methods: Experimental arthritis was induced in wild-type or p21-/- (C57BL/6) mice, using the K/BxN serum-transfer model. Mice were administered p21 peptide mimetics as a prophylactic for arthritis development. Lipopolysaccharide-induced cytokine and signal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex-based assay, flow cytometry, or enzyme-linked immunosorbent assay.

Results: Enhanced and sustained development of experimental inflammatory arthritis, associated with markedly increased numbers of macrophages and severe articular destruction, was observed in p21-/- mice. Administration of a p21 peptide mimetic suppressed activation of macrophages and reduced the severity of experimental arthritis in p21-intact mice only. Mechanistically, treatment with the p21 peptide mimetic led to activation of the serine/threonine kinase Akt and subsequent reduction of the activated isoform of p38 MAPK in macrophages.

Conclusion: These are the first reported data to reveal that p21 has a key role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.

Publication types

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

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Biomimetic Materials / administration & dosage
  • Catalytic Domain / genetics
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / chemistry
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology*
  • Edema / chemically induced
  • Edema / pathology
  • Female
  • Hindlimb
  • Macrophage Activation / drug effects
  • Macrophage Activation / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Peptides / administration & dosage
  • Wound Healing / immunology

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Peptides