PIEZO mechanosensitivity in chondrocytes is differentially modulated by L-type and T-type voltage-sensitive ion channels.

Objective: One of the primary factors contributing to OA development is altered or excessive mechanical stress on the joint, which chondrocytes sense in part through the PIEZO mechanosensitive ion channels. These channels activate signaling pathways that result in joint inflammation and cartilage degeneration. In addition to PIEZO channels, voltage-gated calcium (Ca Design: To better understand the relationship between PIEZO1 and VGCCs, we quantified porcine chondrocytes' intracellular Ca Results: In primary chondrocytes, nifedipine, an L-type VGCC blocker, reduced PIEZO1 sensitivity to both mechanical compression and pharmacological agonism, while NNC-55, a T-type VGCC blocker, increased PIEZO1 activation in response to both stimuli. Similarly, treating cartilage explants exposed to injurious mechanical loads with nifedipine reduced mechanically induced cell death compared to the control, while treatment with NNC-55 increased cell death. Conclusions: In addition to contributing to the current understanding of the mechanisms through which VGCCs modify chondrocyte mechanobiology, our findings suggest the potential of L-type VGCC inhibitors as therapeutic targets for decreasing PIEZO1 signaling and reducing chondrocyte death in response to supraphysiologic mechanical loads.