G protein coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocyte in osteoarthritis via suppression of Piezo1

Abstract

Background Apoptosis of chondrocyte is involved in osteoarthritis (OA) pathogenesis, and mechanical stress plays a key role in this process by activation of Piezo1. However, the negative regulation of signal conduction mediated by mechanical stress is still unclear. Here, we elucidate that the critical role of G protein coupled estrogen receptor (GPER) in the regulation of mechanical stress-mediated signal transduction and chondrocyte apoptosis. Methods The gene expression profile was detected by gene chip upon silencing Piezo1. The expression of GPER in cartilage tissue taken from the clinical patients was detected by RT-PCR and Western blot as well as immunohistochemistry, and the correlation between GPER expression and OA was also investigated. The chondrocytes exposed to mechanical stress were treated with estrogen, G-1, G15, GPER-siRNA and YAP (Yes-associated protein)-siRNA. The cell viability of chondrocytes was measured. The expression of polymerized actin and Piezo1 as well as the subcellular localization of YAP was observed under laser confocal microscope. Western blot confirmed the changes of YAP/ Rho GTPase activating protein 29 (ARHGAP29) /RhoA/LIMK /Cofilin pathway. The knee specimens of osteoarthritis model were stained with safranin and green. OARSI score was used to evaluate the joint lesions. The expressions of GPER and YAP were detected by immunochemistry. Results Expression profiles of Piezo1- silenced chondrocytes showed that GPER expression was significantly upregulated. Moreover, GPER was negatively correlated with cartilage degeneration during OA pathogenesis. In addition, we uncovered that GPER directly targeted YAP and broadly restrained mechanical stress-triggered actin polymerization. Mechanism studies revealed that GPER inhibited mechanical stress-mediated RhoA/LIMK/cofilin pathway, as well as the actin polymerization, by promoting expression of YAP and ARHGAP29, and the YAP nuclear localization, eventually causing the inhibition of Piezo1. YAP was obviously decreased in degenerated cartilage. Silencing YAP caused significantly increased actin polymerization and activation of Piezo1, and an increase of chondrocyte apoptosis. In addition, intra-articular injection of G-1 to OA rat effectively attenuated cartilage degeneration. Conclusion We propose a novel regulatory mechanism underlying mechanical stress-mediated apoptosis of chondrocyte and elucidate the potential application value of GPER as therapy targets for OA.

Baicalein Alleviates Osteoarthritis Progression in Mice by Protecting Subchondral Bone and Suppressing Chondrocyte Apoptosis Based on Network Pharmacology

“…Moreover, molecular docking showed that Bai has high binding affinity for the top targets (BAX, BCL2, and Caspase 3). Accumulating studies have revealed that articular chondrocyte apoptosis occurs under the action of endogenous or exogenous stimulation in patients with OA ( Qiu et al, 2021 ; Sun et al, 2021 ). Chondrocyte apoptosis is one of the important reasons for injury to and loss of articular cartilage and an important mechanism for the occurrence and development of OA ( Wang et al, 2021 ).…”

Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

“…Piezo1 inhibition reduces mechanical shock-induced activation of NLRP3 inflammasome and IL-1β expression in nucleus pulposus cells ( 95 ). In addition, G protein-coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocytes in osteoarthritis via suppression of Piezo1 ( 96 ). Mechanical stretching of the lumbar spine upregulates Piezo1, NLRP3, ASC and IL-1β in nucleus pulposus cells.…”

The Research Advances in G-Protein-Coupled Estrogen Receptor

“…The range of cytoskeletal variation can be modulated by GPER, which is thought to be involved in mechanical transduction [69,70]. When mechanical stress-mediated chondrocyte apoptosis occurs, chondrocyte apoptosis in osteoarthritis can be attenuated by GPER via causing the inhibition of Piezo 1 protein [71].…”