Calcipotriol suppresses GPX4-mediated ferroptosis in OA chondrocytes by blocking the TGF-β1 pathway

Abstract

Globally, tens of millions of individuals experience osteoarthritis (OA), a degenerative joint condition for which a definitive cure is currently lacking. This condition is characterized by joint inflammation and the progressive deterioration of articular cartilage. In this study, western blotting, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analysis were performed to elucidate the molecular mechanisms by which calcipotriol alleviates chondrocyte ferroptosis. The effect of calcipotriol on reactive oxygen species and lipid peroxidation levels in chondrocytes was assessed using dihydroethidium staining and the fluorescent dye BODIPY. To replicate OA, the destabilized medial meniscus model was employed, followed by the injection of calcipotriol into the knee articular cavity. Morphological analysis was conducted through hematoxylin and eosin staining, safranin O-Fast green staining, and micro-computed tomography analysis. Immunohistochemical analysis was performed to validate the effect of calcipotriol in vivo. Our results demonstrate that the expression of SOX9, col2a1, and Aggrecan, as well as MMP13 and ADAMTS5 protein expression levels, decrease upon treatment with calcipotriol in interleukin-1β stimulated chondrocytes. Despite these promising outcomes, the exact mechanism underlying calcipotriol's therapeutic effect on OA remains uncertain. We discovered that calcipotriol inhibits chondrocyte GPX4-mediated ferroptosis by suppressing the expression of transforming growth factor-β1. Furthermore, our study established an in vivo model of OA using rats with medial meniscus instability. Our experiments on rats with OA revealed that intra-articular calcipotriol injection significantly reduces cartilage degradation caused by the disease. Our findings suggest that calcipotriol can mitigate OA by impeding GPX4-mediated ferroptosis of chondrocytes, achieved through the suppression of the TGF-β1 pathway.

Keywords: Calcipotriol; Ferroptosis; GPX4; Osteoarthritis; TGF-β1.