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The stiffness of the pericellular matrix (PCM) decreases in the most common degenerative joint disease, osteoarthritis (OA). This study was undertaken to explore the potential functional role of transient receptor potential vanilloid 4 (TRPV4), Piezo1, and Piezo2 in transducing different PCM stiffness in chondrocytes. Polydimethylsiloxane (PDMS) substrates with different stiffness (designated 197 kPa, 78 kPa, 54 kPa, or 2 kPa, respectively) were first prepared to simulate the decrease in stiffness of the PCM that chondrocytes encounter in osteoarthritic cartilage. Next, the TRPV4-, Piezo1-, or Piezo2-knockdown primary chondrocytes (designated TRPV4-KD, Piezo1-KD, or Piezo2-KD cells) were seeded onto these different PDMS substrates. Then, using a Ca 2+ -imaging system, substrate stiffness-regulated intracellular Ca 2+  influx ([Ca 2+ ]i) in chondrocytes was examined to investigate the role of TRPV4, Piezo1, and Piezo2 in Ca 2+  signaling in response to different stiffness. Results showed that the characteristics of intracellular [Ca 2+ ]iin chondrocytes regulated by PDMS substrate exhibited stiffness-dependent differences. Additionally, stiffness-evoked [Ca 2+ ]ichanges were suppressed in TRPV4-KD, Piezo1-KD, or Piezo2-KD cells compared with control siRNA-treated cells, implying that any channel is fundamental for Ca 2+  signaling induced by substrate stiffness. Furthermore, TRPV4-mediated Ca 2+  signaling played a central role in the response of chondrocytes to 197 kPa and 78 kPa substrate, while Piezo1/2-mediated Ca 2+  signaling played a central role in the response of chondrocytes to 54 kPa and 2 kPa substrate. Collectively, these findings indicate that chondrocytes might perceive and distinguish the different PCM stiffness by using different mechanosensitive ion channels.

The potential role of mechanosensitive ion channels in substrate stiffness-regulated Ca 2+ response in chondrocytes