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.