PIEZO mechanosensitivity in chondrocytes is differentially modulated by L-type and T-type voltage-sensitive ion channels
Year: 2025
Type: article
Abstract: 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 2+ ) channels (VGCCs) have been shown to contribute to Ca 2+ influx into chondrocytes in response to mechanical loads. Design To better understand the relationship between PIEZO1 and VGCCs, we quantified porcine chondrocytes' intracellular Ca 2+ response to mechanical loading or Yoda1 (a PIEZO1 agonist) after various classes of VGCCs were chemically inhibited. We also studied the effects of VGCC blockers on chondrocyte viability in porcine cartilage explants subjected to mechanical compression. 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.
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,610
Awards: G1699998815, G2366089456, Obesity, Biomechanics, and Inflammation in Osteoarthritis, G5330480267, G5588909404, Deconstructing Cartilage Mechanotransduction by Piezo Channels, Viscoelastic Properties of Normal and OA Chondrons, G7008996325, G8840517274, G9000004556, G9000108560, G9000110435, G9000114129, G9000197611, G9000217772, G9000277420, G9000308115, G9000347764, Washington University Rheumatic Diseases Research Resource-based Center, Genetically-engineered stem cells for self-regulating arthritis therapy
OpenAlex ID: W4416443745