PAR2 deletion in the osteoblast lineage affords long-term cartilage protection in experimental osteoarthritis

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Huesa, C. and McGrath, S. and Dunning, L. and Vieri, M.L. and McCulloch, K. and McIntosh, K.A. and Brown, T. and Cole, J.J. and Plevin, R. and Rowan, A.D. and van 't Hof, R. and Ferrell, W.R. and Lockhart, J.C. and Goodyear, C.S. (2026) PAR2 deletion in the osteoblast lineage affords long-term cartilage protection in experimental osteoarthritis. Osteoarthritis and cartilage, 34 (6). pp. 819-831. 819-831. ISSN 1522-9653 (https://doi.org/10.1016/j.joca.2026.03.004)

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Abstract

Objective: Protease-activated receptor 2 (PAR2) plays a pivotal role in the early stages of surgery-induced murine osteoarthritis (OA). However, it remains unclear whether modulation of PAR2 offers sustained, long-term protection against OA progression and which cellular compartments drive pathological changes. Methods: Utilising the destabilization of the medial meniscus model of OA, in vivo and in vitro characterisation of OA pathology was undertaken in global, chondrocyte- or osteoblast-specific PAR2 knockout male mice up to 12 months after OA induction, to reflect end stage OA. Results: Our findings revealed that wild-type mice exhibited a gradual increase in cartilage damage and loss over time, consistent with progressive OA pathology. In contrast, PAR2 knockout mice showed significantly reduced cartilage pathology (MD 4.35, 95%CI 2.55–6.16), indicating a protective effect of PAR2 deletion was maintained with time. Notably, the absence of PAR2 specifically in osteoblasts (MD 2.6, 95%CI 0.5–4.6), but not in chondrocytes (MD 0.61, 95%CI −1.4 to 2.6), resulted in decreased cartilage damage. This suggests that PAR2 expression in osteoblasts plays a critical role in driving joint deterioration during the later stages of OA. Further interrogation of the osteoblast compartment revealed that PAR2 has a divergent role during osteoblast development and maturation compared to its function in differentiated cells. Conclusion: This suggests that PAR2 expression in the bone compartment promotes joint deterioration in later stages of OA, highlighting the importance of bone turnover as a mechanism which influences joint degradation, and the complexity of PAR2-mediated effects, with age-dependent and cell-specific roles.

ORCID iDs

Huesa, C., McGrath, S., Dunning, L., Vieri, M.L., McCulloch, K., McIntosh, K.A. ORCID logoORCID: https://orcid.org/0000-0003-0222-3585, Brown, T., Cole, J.J., Plevin, R. ORCID logoORCID: https://orcid.org/0000-0002-7849-1220, Rowan, A.D., van 't Hof, R., Ferrell, W.R., Lockhart, J.C. and Goodyear, C.S.;
CORE (COnnecting REpositories)