title: Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis.
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.
  
  
  CONCLUSIONS
  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.
authors: Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Melissa
authors: M
authors: Mavers
authors: Carla M
authors: CM
authors: Cuda
authors: Alexander V
authors: AV
authors: Misharin
authors: Angelica K
authors: AK
authors: Gierut
authors: Hemant
authors: H
authors: Agrawal
authors: Evan
authors: E
authors: Weber
authors: Deborah Veis
authors: DV
authors: Novack
authors: G Kenneth
authors: GK
authors: Haines
authors: Dimitrios
authors: D
authors: Balomenos
authors: Harris
authors: H
authors: Perlman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D040761:Biomimetic Materials / Q000008:administration & dosage; D020134:Catalytic Domain / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry / Q000502:physiology*; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006614:Hindlimb; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010455:Peptides / Q000008:administration & dosage; D014945:Wound Healing / Q000276:immunology
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D010455:Peptides