Mechanical stress promotes osteoarthritis progression by increasing miR-145a-5p secretion through Piezo1

Abstract Exosomal microRNAs (miRNAs) are key mediators of intercellular communication and contribute to disease progression, while exosome generation and release can be regulated by mechanical stimuli. Piezo1 is a pivotal mechanosensitive ion channel involved in mechanotransduction; however, how mechanical forces influence exosome-associated signaling and osteoarthritis (OA) progression through Piezo1 remains unclear. In this study, tensile stress was applied to chondrocytes to investigate Piezo1 activation and its downstream effects. Mechanical loading activated Piezo1 and increased intracellular calcium signaling, accompanied by enhanced activation of the transcription factor NFATc1 and increased miR-145a-5p expression. Functional and mechanistic analyses demonstrated that miR-145a-5p directly targeted and suppressed Forkhead box protein O1 (FoxO1), thereby promoting chondrocyte degeneration. Chondrocyte-specific conditional deletion of Piezo1 in Piezo1 flox/flox ; Col2a1 CreERT mice reduced miR-145a-5p expression and attenuated cartilage degeneration in an OA model. Conversely, intra-articular overexpression of miR-145a-5p aggravated cartilage degeneration, whereas inhibition of miR-145a-5p markedly alleviated chondrocyte degeneration and delayed OA progression. Analyses of human osteoarthritic cartilage and longitudinal plasma miRNA data further supported the clinical relevance of miR-145-5p in OA-associated pathological changes. Collectively, these findings identify a mechanotransduction pathway in which mechanical overload activates Piezo1-mediated calcium signaling and NFATc1, leading to increased miR-145a-5p expression and subsequent suppression of FoxO1. Targeting the Piezo1–NFATc1–miR-145a-5p–FoxO1 axis may therefore provide a potential therapeutic strategy for mechanically driven OA.