Depletion of Protease‐Activated Receptor 2 but Not Protease‐Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms. Issue 12 (December 2014)

• Record Type: Journal Article
• Authors: Jackson, Miriam T.; Moradi, Babak; Zaki, Sanaa; Smith, Margaret M.; McCracken, Sharon; Smith, Susan M.; Jackson, Christopher J.; Little, Christopher B.
• Is Part Of: Arthritis & rheumatology. Volume 66:Issue 12(2014)
• Page Start: 3337
• Page End: 3348
• Publication Date: 2014-12
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.38876
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38876-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="art38876-sec-0002" sec-type="section"> <title>Methods</title> <p>OA was induced in the joints of wild‐type (WT), PAR‐1<sup>+/+</sup>, PAR‐1<sup>−/−</sup>, and PAR‐2<sup>−/−</sup> 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.</p> </sec> <sec id="art38876-sec-0003" sec-type="section"> <title>Results</title> <p>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<sup>−/−</sup> mice compared to PAR‐1<sup>−/−</sup> and WT mice.</p> </sec> <sec id="art38876-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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<sup>−/−</sup> 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.</p> </sec> </abstract>