Fibroblast growth factor 10 delays the progression of osteoarthritis by attenuating synovial fibrosis via inhibition of IL-6/JAK2/STAT3 signaling in vivo and in vitro

Osteoarthritis (OA) is a leading cause of disability in the elderly worldwide, and is associated with pain and functional limitation (Quicke et al., 2022). Its main characteristics include degeneration and destruction of cartilage, sclerosis of subchondral bone (Jiang, 2022), and pathological changes of the synovium (Scanzello and Goldring, 2012), including synovitis and synovial fibrosis (Deroyer et al., 2022), which play a critical role in OA progression. In the early phase, synovial tissue hyperplasia promotes the release of inflammatory factors such as interleukin (IL)− 1β, IL-6, and tumor necrosis factor-alpha (TNF-α), accelerating damage to the cartilage and enhancing pain (Liao et al., 2020). Moreover, inflammation stimulates fibroblast-like synoviocytes (FLSs, the main effector cells in synovial fibrosis) proliferation and induces activation of quiescent fibroblasts into myofibroblasts. It has been shown that the expression of mesenchymal markers such as collagen (COL), fibronectin (FN) and α-smooth muscle actin (α-SMA) were increased in myofibroblasts (Rim and Ju, 2020). In addition, prevents the collagen deposition in synovial fibrosis could alleviate the symptoms of OA and prevent the progression of OA (Vaamonde-Garcia et al., 2019). However, no effective therapeutic methods for the treatment of synovial fibrosis have been established for patients with OA until now (Quicke et al., 2022).

Fibroblast growth factor (FGF) 10, a type of multi-functional growth factor, is an evolutionarily-conserved secreted growth factor mediating a mostly epithelial–mesenchymal paracrine signaling pathway (Watson and Francavilla, 2018). In previous studies, FGF10 was found to play a cardinal role in wound healing (Xu et al., 2020), regulating inflammatory responses and alleviating oxidative stress (Watson and Francavilla, 2018). Moreover, compared to other FGFs, FGF10 has prominent anti-fibrotic effects (Hui Et Al, 2018): Varsha V et al. demonstrated that upregulation of FGF10 expression reduces inflammation and attenuates fibrosis and can greatly reduce the extent of bleomycin-induced lung fibrosis (Gupte et al., 2009). Additionally, Hubert et al. showed that conditional FGF10 overexpression promotes cardiomyocyte proliferation and prevents scar formation in the injured ventricle after myocardial infarction, and this effect is reversed by inhibiting FGF10 (Hubert et al., 2022). Beyond that, FGF10 has also been reported to retard the degeneration of articular cartilage, and reduce joint inflammation in a papain-induced OA rat model (Rongshuai et al., 2021). However, the effect of FGF10 on synovial fibrosis progression in OA is still unreported. Therefore, further research is still required.

In this study, human FLSs were isolated from the synovium of OA patients (OA-FLSs) and stimulated with TGF-β (Vaamonde-Garcia et al., 2019) to establish a fibrotic model which was then treated with or without FGF10. Meanwhile, a mouse OA model was also established by surgical destabilization of the medial meniscus (DMM) (Liao et al., 2021) and received FGF10 (or the same volume of vehicle solution) injections into the articular cavity to elucidate the effects of FGF10 on synovial fibrosis of OA in vitro and in vivo. It is our hope that our study, by validating the anti-fibrosis effect of FGF10 in the treatment of OA in in vivo and in vitro studies, will provide the basis for the development of therapies for OA.

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