Depletion of protease-activated receptor 2 but not protease-activated receptor 1 may confer protection against osteoarthritis in mice through extracartilaginous mechanisms

Arthritis Rheumatol. 2014 Dec;66(12):3337-48. doi: 10.1002/art.38876.


Objective: To explore the involvement of protease-activated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice.

Methods: OA was induced in the joints of wild-type (WT), PAR-1(+/+) , PAR-1(-/-) , and PAR-2(-/-) mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks post-DMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/activity were studied in cultures of mouse femoral head tissue with or without interleukin-1α (IL-1α). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry.

Results: Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1α-induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4+ T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2(-/-) mice compared to PAR-1(-/-) and WT mice.

Conclusion: Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMM-induced cartilage damage. The chondroprotection in PAR-2(-/-) mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • Aggrecans / genetics
  • Aggrecans / metabolism
  • Animals
  • Cartilage, Articular / metabolism*
  • Chondrocytes / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics*
  • Menisci, Tibial / surgery*
  • Metalloproteases / genetics*
  • Metalloproteases / metabolism
  • Mice
  • Mice, Knockout
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Protective Factors
  • Proteoglycans / metabolism
  • RNA, Messenger / analysis*
  • Receptor, PAR-1 / genetics*
  • Receptor, PAR-2 / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Aggrecans
  • Proteoglycans
  • RNA, Messenger
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Metalloproteases
  • ADAM Proteins