Exercise therapy-associated changes in Periostin (POSTN) osteoarthritis are linked to Hippo-YAP signaling

Osteoarthritis (OA) is characterized by progressive extracellular matrix (ECM) degradation, chondrocyte apoptosis, and hypertrophic differentiation, yet the molecular basis underlying the protective effects of exercise therapy remains incompletely understood. Given that periostin (POSTN) is a mechanosensitive extracellular matrix protein implicated in OA progression and that Hippo-YAP signaling is a key regulator of mechanotransduction and cartilage homeostasis, their potential involvement in exercise-mediated chondroprotection warrants investigation.

This study aims to investigate the association between exercise therapy and osteoarthritis progression, with a focus on POSTN and the Hippo-YAP signaling pathway.

Bioinformatics analysis was performed using the GSE169077 dataset to identify candidate genes in OA. An anterior cruciate ligament transection (ACLT)-induced rat OA model with treadmill exercise intervention and an IL-1β-induced OA-like C28/I2 chondrocyte model with cyclic tensile strain (CTS) stimulation were established. POSTN expression was detected by RT-qPCR, Western blot, and immunohistochemistry. The roles of POSTN and Hippo-YAP signaling pathways in ECM metabolism, apoptosis, hypertrophic differentiation, and YAP nuclear translocation were evaluated by POSTN overexpression and vertexporfin-mediated YAP inhibition.

Bioinformatics analysis identified COL1A1, MMP2, MMP9, and POSTN as upregulated genes in OA. POSTN expression was increased in both rat OA cartilage and IL-1β-induced OA-like chondrocytes and was significantly suppressed by exercise intervention in vivo and CTS in vitro. In interleukin-1β (IL-1β)-induced OA-like chondrocytes, CTS reduced the expression of matrix degradation-related proteins (ADAMTS5 and MMP13), increased Aggrecan and Collagen II levels, inhibited apoptosis (decreased Bax, Cytochrome c, and cleaved caspase-3 and increased Bcl-2), and attenuated hypertrophic differentiation (decreased RUNX2 and COL10A1 and increased SOX9). These protective effects were partially reversed by POSTN overexpression. Mechanistically, CTS decreased the p-LATS1/LATS1 and p-YAP/YAP ratios, restored YAP expression, and promoted its nuclear translocation, whereas POSTN overexpression attenuated these effects. Furthermore, verteporfin exacerbated POSTN overexpression-induced extracellular matrix degradation and hypertrophic differentiation. Consistent with the in vitro findings, exercise intervention in vivo reduced the expression of the hypertrophic markers MMP13 and RUNX2 while restoring the expression of SOX9, Collagen II, and YAP in OA cartilage.

These findings suggest that exercise therapy may be associated with changes in chondrocyte catabolic and hypertrophic processes in osteoarthritis, potentially involving the suppression of POSTN and modulation of the Hippo-YAP signaling pathway.