Elevated expression of Piezo1 activates the cGAS-STING pathway in chondrocytes by releasing mitochondrial DNA.

Abstract

Objective: Abnormal mechanical stress is a key factor in osteoarthritis (OA) pathogenesis. This study aims to investigate the role of the mechanosensitive ion channel Piezo1 in activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and its contribution to cartilage degradation in OA.

Methods: We conducted both in vivo and in vitro experiments. In vitro, chondrocytes were subjected to mechanical stress, and Piezo1 expression, calcium ion (Ca²⁺) influx, and mitochondrial permeability changes were analyzed. In vivo, Piezo1 conditional knockout (Col2a1^CreERT; Piezo1^flox/flox) mice were used to assess the activation of the cGAS-STING pathway and cartilage degradation. Additionally, the effects of STING inhibitors on inflammation and OA progression were evaluated.

Results: Mechanical stress significantly increased Piezo1 expression and Ca²⁺ influx in chondrocytes, leading to mitochondrial Ca²⁺ overload and mitochondrial DNA (mtDNA) release. This triggered activation of the cGAS-STING pathway (9.35[95%Confidence Interval (CI) 1.378 to 18.032], n=3 biologically independent samples), resulting in inflammatory responses (4.185[95%CI 0.411 to 8.168], n=3 biologically independent samples). In Piezo1 knockout mice, cGAS-STING activation (-7.23[95%CI -10.52 to -3.89], n=6) and cartilage degradation (Osteoarthritis Research Society International (OARSI) grade; -3.651[95%CI -5.562 to -1.681] n=6) were reduced. STING inhibitors effectively decreased inflammation (-8.95[95%CI -17.24 to -1.31], n=3 biologically independent samples) and slowed OA progression (OARSI grade; -2.76 [95%CI -4.37 to -1.08], n=6) in both in vivo and in vitro models.

Conclusions: Mechanical stress induces mtDNA release via Piezo1 activation, which triggers the cGAS-STING pathway and exacerbates cartilage degradation. Targeting Piezo1 or the cGAS-STING pathway may offer a promising therapeutic strategy to reduce inflammation and protect cartilage in OA.