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

Protease-activated receptor 2 (PAR2) plays a pivotal role in the early stages of surgery-induced murine osteoarthritis OA. It remains to be determined however, whether PAR2 contributes to later stages of disease pathology and which cellular compartments drive pathological changes. Thus, we characterised OA pathology in global, chondrocyte- or osteoblast-specific PAR2 knockout mice up to 12 months after OA induction. While wild-type mice display a gradual increase in cartilage damage/loss, PAR2 knockout mice had significantly reduced cartilage pathology. Notably, removing PAR2 specifically in osteoblasts, but not in chondrocytes, substantially improved cartilage health. Interrogation of the osteoblast compartment revealed that PAR2 has a divergent role during osteoblast development and maturation compared to its function in already differentiated cells. This suggests that PAR2 expression in the bone compartment promotes joint deterioration in later stages of OA, highlighting the important role of bone in OA and the therapeutic potential of targeting PAR2.