miR‐373 regulates inflammatory cytokine‐mediated chondrocyte proliferation in osteoarthritis by targeting the P2X7 receptor

Abstract

Inflammatory cytokines commonly initiate extreme changes in the synovium and cartilage microenvironment of osteoarthritis ( OA ) patients, which subsequently cause cellular dysfunction, especially in chondrocytes. It has been reported that induction of the purinergic P2X7 receptor (P2X7R) can regulate the expression of a variety of inflammatory factors, including interleukin ( IL )‐6 and ‐8, leading to OA pathogenesis. However, knowledge of the mechanism of upregulation of P2X7R in OA is still incomplete, and its role in chondrocyte proliferation is also not clear. It was reported previously that the expression of P2X7R was controlled by certain micro RNA s, and so we tested the expression of several micro RNA s and found that microRNA‐373 (miR‐373) was downregulated in the chondrocytes from OA patients. Regarding the mechanism of action, miR‐373 inhibited chondrocyte proliferation by suppressing the expression of P2X7R, as well as inflammatory factors such as IL ‐6 and IL ‐8. Furthermore, the proliferative and pro‐inflammatory effects of miR‐373 on the chondrocytes could be suppressed by a P2X7R antagonist, further suggesting that miR‐373 mediates chondrocyte proliferation and inflammation by targeting P2X7R. Generally, our results suggest a novel method for OA treatment by targeting the miR‐373–P2X7R pathway.

The Role of Inflammation in the Pathogenesis of Osteoarthritis

“…IL-6 transsignaling will skew the differentiation of monocytes to macrophages through the upregulation of the macrophage colony-stimulating factor (M-CSF) receptor [45]. A significant increase of IL-6 and IL-8 has been observed in patients with osteoarthritis [46][47][48][49][50][51]. For instance, Favero et al determined the inflammatory molecules produced from coculture of meniscus tissue and synovial membrane from patients with early-stage (n = 5) and end-stage (n = 5) osteoarthritis [47].…”

“…NF-κB is the downstream signaling pathway of TAK1; thus, upregulated TAK1 causes increased activation of NF-κB in osteoarthritis [104]. Zhang et al demonstrated that miR-373 decreased in osteoarthritis and it targeted P2X7 receptor (P2X7R) [49]. P2X7R expression was enhanced in osteoarthritis; this led to increased chondrocyte proliferation and release of inflammatory factors such as IL-6 and IL-8.…”

Effects of miR-146a-5p on chondrocyte interleukin-1β-induced inflammation and apoptosis involving thioredoxin interacting protein regulation

“…8 As an example, miR-373 expression was reported to be downregulated in OA patient chondrocytes, while its overexpression promoted chondrocyte proliferation by inhibiting the expression of P2X7 receptor and inflammatory factors. 2 Interleukin (IL)-1b also promoted the occurrence of OA and degradation of the ECM through regulating the mitogen-activated protein kinase/nuclear factor-jB pathway by inhibiting miR-27a-3p. 9 Recently, miR-146a-5p was shown to play an important regulatory role in a variety of tumors, including gastric cancer, lung cancer, and prostate cancer.…”

Mesenchymal Stromal Cell-Derived Extracellular Vesicles – Silver Linings for Cartilage Regeneration?

“…Cartilage-protective effects are mediated by miR-140 via targeting ADAMTS5, MMP13 and HDAC4 driving expression of COL2A1 and ACAN ( Tuddenham et al, 2006 ; Miyaki et al, 2009 ; Si et al, 2020 ). OA progression is accompanied by decreased miR-337 expression and loss of miR-337 shifts the equilibrium from anabolism of cartilage tissue to bone formation, ( Zhang et al, 2018b ). Studies frequently find more upregulated than downregulated miRNAs in OA ( Ntoumou et al, 2017 ; Coutinho, de Almeida et al, 2019 ).…”