Background Osteoarthritis (OA) is a common chronic disease characterized by chronic inflammation and extracellular matrix degradation. Indole-3-propionic acid (IPA) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in a variety of diseases. In this study, we further investigated the potential therapeutic role of IPA in OA and the underlying mechanism. Methods IL-1β was utilized to induce chondrocyte inflammation. Then, the cytotoxicity of IPA on rat chondrocytes was assessed. Meanwhile, RT-qPCR, Griess reaction, ELISA, Western blot and immunofluorescence were performed to evaluate the expression of inflammatory factors and stromal proteins, and the NF-κB pathway in chondrocytes treated with IL-1β alone, with IPA or with aryl hydrocarbon receptor (AhR) knockdown. An OA rat model was established by anterior cruciate ligament transection, and hematoxylin-eosin staining, Safranin-O/Fast Green staining and immunochemistry were applied to estimate OA severity. Results IPA did not affect cellular viability at concentrations up to 80 µM. IPA significantly inhibited the IL-1β-induced expression of inflammatory factors (Nitric oxide, PGE2, TNF-α, IL-6, iNOS and COX-2) and matrix-degrading enzymes (MMP-3, MMP-13 and ADAMTS-5), upregulated the expression of anabolic markers (aggrecan and collagen-II) and inactivated the NF-κB pathway. However, AhR knockdown could abolish the above protection capabilities and the suppression of the NF-κB pathway induced by IPA. Furthermore, IPA significantly reduced serum inflammatory cytokines expression, cartilage destruction and synovitis in vivo, demonstrating its protective role in OA progression. Conclusion IPA improved IL-1β-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.

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Excessive mechanical strain is the prominent risk factor for osteoarthritis (OA), causing cartilage destruction and degeneration. However, the underlying molecular mechanism contributing to mechanical signaling transduction remains unclear in OA. Piezo type mechanosensitive ion channel component 1 (Piezo1) is a calcium-permeable mechanosensitive ion channel and provides mechanosensitivity to cells, but its role in OA development has not been determined. Herein, we found up-regulated expression of Piezo1 in OA cartilage, and that its activation contributes to chondrocyte apoptosis. The knockdown of Piezo1 could protect chondrocytes from apoptosis and maintain the catabolic and anabolic balance under mechanical strain. In vivo, Gsmtx4, a Piezo1 inhibitor, markedly ameliorated the progression of OA, inhibited the chondrocyte apoptosis, and accelerated the production of the cartilage matrix. Mechanistically, we observed the elevated activity of calcineurin (CaN) and the nuclear transfection of nuclear factor of activated T cells 1 (NFAT1) under mechanical strain in chondrocytes. Inhibitors of CaN or NFAT1 rescued the pathologic changes induced by mechanical strain in chondrocytes. Overall, our findings revealed that Piezo1 was the essential molecule response to mechanical signals and regulated apoptosis and cartilage matrix metabolism via the CaN/NFAT1 signaling axis in chondrocytes, and that Gsmtx4 could be an attractive therapeutic drug for OA treatment.

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