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- Title
Depletion of Protease-Activated Receptor 2 but Not Protease-Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms.
- Authors
Jackson, Miriam T.; Moradi, Babak; Zaki, Sanaa; Smith, Margaret M.; McCracken, Sharon; Smith, Susan M.; Jackson, Christopher J.; Little, Christopher B.
- Abstract
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.
- Subjects
OSTEOARTHRITIS; ARTICULAR cartilage; ANIMAL experimentation; ARTHRITIS; CELL receptors; FLOW cytometry; GENE expression; GENETICS; MICE; PROTEOLYTIC enzymes; RHEUMATOLOGY; RNA; SERIAL publications; SYNOVIAL fluid; SYNOVIAL membranes; CD4 antigen; GENOTYPES; ANATOMY; PREVENTION
- Publication
Arthritis & Rheumatology, 2014, Vol 66, Issue 12, p3337
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.38876