Osteoarthritis (OA) is characterized by cartilage degradation, subchondral bone (SB) osteosclerosis and osteophyte formation. Proteinase-activated receptor-2 (PAR2) plays an important role in experimental OA as cartilage breakdown is reduced either in PAR2-/- mice or by inhibition of this receptor in wild-type (WT) mice. This study examines SB changes in murine OA and how it is influenced by PAR-2 deficiency. OA was induced by destabilization of the medical meniscus (DMM) and bone assessed in ipsilateral and contralateral joints by μCT after 3, 7, 14 and 28 days in WT mice, and at day 14 and 28 in PAR-2-/- mice (n=6-8/group). In WT mice, SB expansion was observed by day 28 as a distinct second cortical layer on the medial side of the subchondral plate, which emerged at day 7 as small osteophytes along the medial side, growing in size and density by day 14. Histology showed that the emergence of these mineralised osteophytes was chondrocyte driven. SB expansion was associated with protruding osteophytes in 92.3% of WT, yet only in 45.5% of PAR2-/- mice, and the latter were significantly smaller (WT=2.50±0.27, PAR2-/-=0.41±0.19 μm3) and more dense (WT=60.3±3.95, PAR2-/-=74.3±3.05%). Osteosclerosis was significant by day 14 in WT (P=0.023) and remained so at day 28 (P=0.019) whilst PAR2-/- mice showed no significant osteosclerosis at either day 14 or 28. Cartilage damage was not significant until day 28 in WT compared to sham (P=0.005), whilst PAR2-/- mice did not differ from sham operated mice. Osteophytes develop early in the DMM model, prior to cartilage degradation. This is dependent on PAR2 since osteophyte formation and osteosclerosis were reduced in PAR2-/- mice. As these bone changes precede cartilage damage, secondary cartilage changes cannot cause or mediate such bone changes, raising the intriguing question whether these directly contribute to subsequent cartilage pathology.
Disclosure: This work was supported by Arthritis Research UK (grant number 20199).