The emerging role of fibroblast-like synoviocytes-mediated synovitis in osteoarthritis: An update

Abstract

Osteoarthritis (OA), the most ubiquitous degenerative disease affecting the entire joint, is characterized by cartilage degradation and synovial inflammation. Although the pathogenesis of OA remains poorly understood, synovial inflammation is known to play an important role in OA development. However, studies on OA pathophysiology have focused more on cartilage degeneration and osteophytes, rather than on the inflamed and thickened synovium. Fibroblast-like synoviocytes (FLS) produce a series of pro-inflammatory regulators, such as inflammatory cytokines, nitric oxide (NO) and prostaglandin E₂ (PGE₂ ). These regulators are positively associated with the clinical symptoms of OA, such as inflammatory pain, joint swelling and disease development. A better understanding of the inflammatory immune response in OA-FLS could provide a novel approach to comprehensive treatment strategies for OA. Here, we have summarized recently published literatures referring to epigenetic modifications, activated signalling pathways and inflammation-associated factors that are involved in OA-FLS-mediated inflammation. In addition, the current related clinical trials and future perspectives were also summarized.

Keywords: clinical trials; epigenetics; fibroblast-like synoviocytes; osteoarthritis; synovitis.

FIGURE 1

MiRNAs involved in OA‐FLS inflammation. TGF‐β1 enhanced FOXO3‐induced anti‐inflammatory effects in human OA‐FLS by suppressing miR‐92a through AMPK and p38 signalling pathway. TGF‐β1 promoted anti‐inflammatory HO‐1 generation in human OA‐FLS by blocking the synthesis of miR‐519b. Adipokine resistin enhanced the generation of MCP‐1 and promoted monocyte migration in human OA‐FLS by inhibiting miR‐33a and miR‐33b through activated PI3K/AKT/mROT signalling pathway. Adipokine visfatin enhanced IL‐6 and TNF‐α expression in human OA‐FLS by inhibiting miR‐199a‐5p via ERK, p38 and JNK signalling pathways. Soya‐cerebroside down‐regulated MCP‐1 expression in OA‐FLS by increasing miR‐432 through activated AMPK/AKT signalling pathway. PLCγ: Phospholipase Cγ; PKCα: Protein kinase C alpha; SP1: Specificity protein 1; VEGF: Vascular endothelial growth factor; MCP‐1/CCL2: Monocyte chemoattractant protein‐1/C‐C motif ligand 2

FIGURE 2

DNA methylation and histone acetylation involved in OA‐FLS inflammation. 5‐AzadC, a DNA methyltransferase inhibitor, up‐regulated miR‐146a by decreasing binding affinity between NF‐κB transcription factors and the hypermethylated miR‐146a regulatory regions. Dnmt3a, a DNA methyltransferase, increased the IL‐6 promoter methylation then suppressed IL‐6 production. Anacardic acid, a histone acetyltransferase inhibitor, decreased histone acetylation and binding of HAT1 and CBP on the IL‐6 promoter then suppressed IL‐6 expression. leptin promoted IL‐8 expression through the leptin receptor (OBRI), JAK2, STAT3 pathway as well as the initiation of IRSI, PI3K, Akt, NF‐κB‐dependent pathway and the following recruitment of p300. 15d‐PGJ2 inhibited IL‐1β‐induced COX‐2 production by suppressing H3 acetylation at the COX‐2 promoter through repressed HAT p300 recruitment. HDAC inhibitors (SAHA, LBH589) promoted the binding between the transcription factor NF‐κB and the miR‐146a promoter, subsequently increasing miR‐146a expression levels. Denbinobin increased miR‐146a expression, leading to a decreased monocyte adhesion by reducing the IL‐1β‐induced ICAM‐1, VCAM‐1 through regulated NF‐κB‐binding sites positioned within the miR‐146a promoter region. Anacardic acid attenuated denbinobin‐mediated increase in the HAT activity, histone H3 acetylation at both the NF‐κB‐binding sites and miR‐146a expression. HDAC4 promoted IL‐1‐induced mPGES‐1 production by up‐regulation of Egr‐1 transcriptional activity

FIGURE 3

Activated NF‐κB signalling pathway in OA‐FLS inflammation. CTGF promoted the generation of IL‐6 in human OA‐FLS through the ανβ5 integrin, ASK1, p38/JNK and AP‐1/NF‐kB signal transduction pathways. CTGF‐induced IL‐β in human OA‐FLS through αvβ3/ανβ5 integrins, ROS, and ASK1, p38/JNK, and NF‐κB signal transduction pathways, which attenuated by berberine, an anti‐inflammatory isoquinoline alkaloid separated from the Chinese herb Rhizoma coptidis (Huang Lian). CTGF enhanced MCP‐1 production in human OA‐FLS through the ανβ5 integrin, FAK, MEK, ERK and NF‐κB/AP‐1 signalling pathway. FSLT1 elevated TNF‐α, IL‐1β and IL‐6 generation in human OA‐FLS via activated NF‐κB signalling pathway. FSLT1 increased OA‐FLS proliferation by down‐regulating p53 and p21. Moreover, p21 was reported to block the elevated IL‐6 and MMPs, participated in the development of OA. WY‐14643, an agonist of PPAR‐α, decreased LPS‐induced NO, PGE2, inflammatory mediators (VCAM‐1, ICAM‐1, ET‐1 and TF), and pro‐inflammatory cytokines (IL‐6, IL‐1β, TNF‐α and MCP‐1) production in human OA‐FLS by suppressing LPS‐mediated NF‐κB activation and IkB phosphorylation. p53, a tumour‐suppressor protein. p21, a cyclin‐dependent kinase inhibitor

FIGURE 4

Wnt/β‐catenin signalling pathway in OA‐FLS inflammation. FoxC1, a target gene of miR‐200a‐3p, promoted human OA‐FLS proliferation, pro‐inflammatory cytokine and catabolic enzymes expression by elevated β‐catenin production. IL‐1β inhibited miR‐200a‐3p enhanced the effects of FoxC1 in human OA‐FLS. XAV‐939, a small‐molecule inhibitor of Wnt pathway, reduced proliferation and I collagen levels of OA‐FLS. Lorecivivint, a small‐molecule Wnt pathway inhibitor, declined pro‐inflammatory cytokines by inhibiting NF‐κB and STAT3 phosphorylation through reduced CLK2 and DYRK1A production in human OA‐FLS. LRP5/6: Lipoprotein receptor‐associated protein; GSK3β: Glycogen synthase kinase 3β; CK1: Casein kinase 1; APC: Adenomatous polyposis coli; LEF/TCF: Lymphoid enhancer factor/T‐cell; CLK2: CDC‐like kinase 2; DYRK1A: Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A