Signalling and putative therapeutic molecules on the regulation of synoviocyte signalling in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA. Cite this article: Bone Joint Res 2021;10(4):285-297.

Keywords: Hyperplasia; Inflammation; Joint destruction; Rheumatoid arthritis; Synoviocytes.

Fig. 1

Schematic diagram of the overall signalling mechanism and related factors of proliferative and apoptotic modulation in the fibroblastic synoviocytes (FLS) of rheumatoid arthritis (RA). Proliferation and apoptosis in FLS are regulated by various signalling factors. IL-36α, NCL, SAHA, and MMC increase reactive oxygen species (ROS) and survivin activates platelet-derived growth factor (PDGF) signalling. PDGF and ROS affect extracellular signal‑regulated protein kinase 1/2 (ERK1/2), p38, phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) signalling. SAHA inhibits B-cell lymphoma-extra large (Bcl-xL) and myeloid cell leukemia-1 (Mcl-1) expression. NCL inhibits nuclear factor kappa-B (NF-κB). Quercetin and hesperidin inhibit extracellular signal-regulated kinase (ERK)/PI3K/Akt signalling, whereas IL-36α, IL-32γ, IL-21, IL-27, LTα, and C43 activate this signalling. While calreticulin stimulates Bcl-xL, Mcl-1, and C-X-C motif chemokine ligand (CXCL)-1/8 through this signalling, ATO and resveratrol enhance caspase-8 activity, and CYLD, SAA, LIGHT, and TGF-β1 activate NF-κB signalling. In the nucleus, Shh activates MCP-1 and CYLD and DLL-1 increase MMPs and IL-1β through NF-κB signalling. GPI, APRIL, and RasGRPs increase inflammatory factors such as TNF-α and IL-8. JMJD3 inhibits the activity of PCNA in the nucleus. SAHA and DMHP enhance expression of Bcl-2-associated X protein (BAX) and caspase-3, and they also attenuate Bcl-2 expression. LIGHT, lymphotoxin-like, herpes simplex virus glycoprotein D, a receptor expressed by T lymphocytes; LTα, lymphotoxin α; APRIL, a proliferation-inducing ligand; Shh, Sonic hedgehog; GPI, glucose-6-phosphate isomerase; IL, interleukin; JMJD3, Jumonji C family of histone demethylases; CYLD, cylindromatosis; RasGRPs, Ras guanine nucleotide-releasing proteins; TGF-β1, transforming growth factor-β1; SAA, serum amyloid A; DLL-1, δ like Notch ligand 1; C43, compound 43; ATO, arsenic trioxide; DMHP, 7,3'-dimethoxy hesperetin; NCL, niclosamide; MMC, mitomycin C; MCP-1, monocyte chemoattractant protein-1; SAHA, suberoylanilide hydroxamic acid; PCNA, proliferating cell nuclear antigen.

Fig. 2

Schematic diagram of the overall signalling mechanism and related factors of inflammatory activity, migration, and invasion in the fibroblastic synoviocytes (FLS) of rheumatoid arthritis (RA) FSTL1 stimulates JAK signalling. Oxymatrine and C3G enhance FAK signalling. Anti-CCP antibody activates PI3K. JAK induces activation of extracellular signal‑regulated protein kinase 1/2 (ERK1/2) and pSTAT3, FAK activates phosphoinositide 3-kinase (PI3K), p38, and protein kinase B (Akt) signalling. Chemerin and GRP activate PI3K/Akt signalling, but CA-074Me inhibits this signalling. HIP-1 activates RAC1 and HDAC5 activates interferon regulatory factor 1 (IRF-1) through PI3K/Akt signalling. HDAC6 inhibits inflammatory factors such as interleukin (IL)-6 and tumour necrosis factor-α (TNF-α) through nuclear factor kappa-B (NF-κB) transcription in the nucleus, whereas class 3 semaphorins increase levels of matrix metalloproteinases (MMPs). In addition, increased TNF-α enhances DKK-1 and FAK. This signalling is involved in the inflammation, migration, and invasion of FLS. C3G, cyanidin-3-glucoside; DKK-1, Dickkopf-1; FAK: integrin-related focal adhesion kinase; pSTAT3: phosphorylated signal transducer and activator of transcription 3; GRP, gastrin-releasing peptide; HIP-1, Huntingtin-interacting protein-1; HDAC, histone deacetylase; FSTL1, follistatin-like protein 1; ECM proteins, extracellular matrix proteins; anti-CCP, anti-cyclic citrullinated peptide.