Upregulation of stanniocalcin‐1 inhibits the development of osteoarthritis by inhibiting survival and inflammation of fibroblast‐like synovial cells

Abstract

Objective Osteoarthritis (OA) is a progressive and disabling disorder, characterized by synovial inflammation and joint effusion. This study aimed to explore the role of stanniocalcin-1 (STC1) in the development of OA by regulating the survival and inflammation of fibroblast-like synovial (FLS) cells.Methods Microarray analyses were adopted to screen differentially expressed genes (DEGs) related to OA, and regulatory microRNA (miR) was also identified. Synovial tissue samples from patients with OA and healthy individuals were obtained to determine the expression levels of miR-454, STC1, IL-6, IL-8, and MMP3/13. The targeted relationship between miR-454 and STC1 was verified by dual-luciferase reporter gene assay. With the treatment of miR-454 mimic and STC1 overexpression vector, the effect of miR-454 and STC1 on FLS cell viability and apoptosis as well as production of inflammatory cytokines were tested. Results STC1 with aberrant low expression was screened from GSE1919 profile in OA. STC1 was found to be downregulated in OA-FLS tissues and cells. STC1 overexpression inhibited OA-FLS cell viability but induced apoptosis of OA-FLS cells. Moreover, STC1 overexpression decreased levels of IL-6, IL-8, and MMP3/13, suggesting that STC1 overexpression suppressed inflammatory reactions. In addition, miR-454 blocked the inhibitory effects of STC1 overexpression on OA-FLS cell viability and inflammatory reaction and exerted a promotion effect of STC1 overexpression on apoptosis of OA-FLS cells.Conclusions Taken together, the results revealed that upregulation of STC1 could repress proliferation of OA-FLS cells and inflammatory reaction, and enhance apoptosis of OA-FLS cells, which was negatively regulated by miR-454. K E Y W O R D Sapoptosis, fibroblast-like synovial cells, inflammation, osteoarthritis, proliferation, stanniocalcin-1

The Role of Inflammation in the Pathogenesis of Osteoarthritis

“…Other than that, several studies showed increased MMP-3 in osteoarthritis [47,48,53,73,78,82,83]. The induction of MMP-3 has been related to miR-149 and miR-454 expression in osteoarthritis [51,84].…”

“…Conversely, overexpression of IL-37 in chondrocytes decreased the MMP-13 level [53]. Two separate studies by Zhang et al and Wu et al showed that changes in microribonucleic acid (miRNA) expression in osteoarthritis could alter the MMP-13 level [35,51]. They found that miR-502-5p and miR-454 enhanced the MMP-13 level.…”

“…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].…”

“…Recent human studies highlighted that miR-381a-3p [31] and miR-454 [51] were upregulated in osteoarthritis. Xia et al discovered that nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor alpha (IκBα) is a target gene of miR-381a-3p [31].…”

“…Hence, upregulation of miR-381a-3p will decrease IκBα expression and further enhance the activation of NF-κB. Wu et al showed that miR-454 overexpression in osteoarthritis promoted the proliferation of synovial fibroblasts and increased inflammatory factors [51].…”