Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

TLDR

Cartilage is a mechanically sensitive tissue whose chondrocytes transduce mechanical stimuli, and high‑strain mechanotransduction contributes to osteoarthritis, yet the underlying molecular mechanisms remain unclear. The study aims to identify Piezo1 and Piezo2 ion channels as the transduction mediators of high‑strain mechanical stress in chondrocytes. The authors demonstrate that Piezo1 and Piezo2 are functionally linked to the cytoskeleton, enabling their concerted activity, and they test a blocking peptide, GsMTx4, as a potential therapeutic. They confirm the cytoskeletal coupling of Piezo1/2 and show that GsMTx4 effectively blocks their activity, suggesting a remedial strategy for cartilage mechanotrauma.

Abstract

Significance Cartilage, a mechanically sensitive tissue that covers joints, is essential for vertebrate locomotion by sustaining skeletal mobility. Transduction of mechanical stimuli by cartilage cells, chondrocytes, leads to biochemical–metabolic responses. Such mechanotransduction can be beneficial for tissue maintenance when evoked by low-level mechanical stimuli, or can have health-adverse effects via cartilage-damaging high-strain mechanical stress. Thus, high-strain mechanotransduction by cartilage mechanotrauma is relevant for the pathogenesis of osteoarthritis. Molecular mechanisms of high-strain mechanotransduction of chondrocytes have been elusive. Here we identify Piezo1 and Piezo2 mechanosensitive ion channels in chondrocytes as transduction channels for high-strain mechanical stress. We verify their functional link to the cytoskeleton as important for their concerted function and offer a remedial strategy by application of a Piezo1/2 blocking peptide, GsMTx4, from tarantula venom.