Limited roles of Piezo mechanosensing channels in articular cartilage development and osteoarthritis progression

Abstract

Osteoarthritis (OA) is a prevalent disease characterized by degeneration of the joint and pain. Mechanical stress plays a central role in OA development. It is hypothesized that cells in the OA joints produce OA-promoting molecules upon mechanical stress, and therefore, the mechanosensing systems are a theoretical target for OA treatment. Piezo mechanosensing channels mediate high-level mechanical stress in chondrocytes and have been suggested to play an important role during OA progression. To test this hypothesis, we ablated Piezo1 and Piezo2 in joint tissues using Gdf5-Cre transgenic mice [Piezo1 and 2 doubly conditional knockout (cKO) mice, cKO mice]. cKO mice showed normal development of knee joints. Both control and cKO mice developed modest to severe OA 12 weeks after the induction of OA, although some cKO mice showed milder OA. We did not find significant differences in pain in mice or gene expression after fluid flow stress in primary cells between control and cKO. Our data demonstrate the limited role of Piezo channels in joint development and OA progression. SummaryO_ST_ABSObjectiveC_ST_ABSTo investigate the role of Piezo1 and Piezo 2 in surgically induced osteoarthritis (OA) in mice. DesignMale conditional knockout (cKO) mice missing Piezo1 and Piezo2 in the joint via Gdf5-Cre transgenic mice were induced post-traumatic osteoarthritis (OA) by destabilization of the medial meniscus (DMM) of the right knee joint at 12 weeks of age. The severity of OA was assessed at 24 weeks of age using a modified Osteoarthritis Research Society International (OARSI) scoring system. OA-associated pain was evaluated by static weight bearing analysis at 4, 8, and 12 weeks post-operation. Additionally, articular chondrocytes isolated from cKO mice were exposed to fluid flow shear stress (FFSS) to evaluate the expression of OA-associated genes. ResultsMice with conditional deletion of Piezo1 and Piezo 2 showed normal joint development with no overt histological changes in the knee joint at 12 weeks and 24 weeks. DMM surgery induced moderate to severe OA in both control and cKO mice, although a few cKO mice showed milder OA. Pain assessment by static weight-bearing analysis suggested Piezo ablation in the joint has no beneficial effects on pain. FFSS increased the expression of OA-related genes both in control and cKO mice to similar extents. ConclusionPiezo1 and Piezo2 are not essential for normal joint development. Genetic ablation of Piezo channels did not confer evident protective effects on OA progression in mice. In vitro data suggests that different mechanotransducers other than Piezo channels mediate FFSS in mechanical stress-induced gene expression.