Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial Fibroblasts

Abstract

Objective Optineurin (OPTN) is an autophagy adaptor/receptor that acts as an intrinsic negative regulator of osteoclast differentiation. RANKL expressed by rheumatoid arthritis synovial fibroblasts (RASFs) is primarily responsible for the development of bone erosions in patients with RA. The aim of the present study was to explore the role of OPTN in the pathogenesis of joint destruction in RA. Methods RASFs were left untreated or incubated with tumor necrosis factor (TNF) or interferon‐γ (IFNγ), and expression of OPTN by RASFs was analyzed by reverse transcription–quantitative polymerase chain reaction (RT‐qPCR) and Western blotting. Expression of RANKL and osteoprotegerin (OPG) was evaluated in cultures of OPTN‐reduced RASFs with or without TNF or IFNγ treatment. OPTN‐reduced RASFs were cocultured with monocytes and stained for tartrate‐resistant acid phosphatase (TRAP). IκBα, NF‐κB1, and RelA protein levels were measured to evaluate NF‐κB signaling. Expression of messenger RNA (mRNA) for matrix metalloproteinase 3 (MMP3), interleukin‐6 (IL6), GATA binding protein 3 (GATA3), carbohydrate sulfotransferase 15 (CHST15), hyaluronan synthase 1 (HAS1), and GATA1 was analyzed by RT‐qPCR. Results In RASFs incubated with TNF or IFNγ, OPTN expression was up‐regulated and RANKL expression was increased, and these effects were further pronounced in OPTN‐reduced RASFs (all P < 0.05 versus controls). OPG mRNA levels remained unchanged. Monocytes cocultured with OPTN‐reduced RASFs differentiated to a greater extent into TRAP+ multinucleated cells compared to monocytes cocultured with control RASFs (P < 0.05). IκBα degradation and nuclear NF‐κB1 expression following TNF treatment were both prolonged in OPTN‐reduced RASFs (each P < 0.05 versus controls). MMP3 mRNA levels were up‐regulated, while GATA3, CHST15, and HAS1 mRNA levels were down‐regulated in OPTN‐reduced RASFs (each P < 0.05 versus controls). Conclusion OPTN plays a protective role in RA when it is up‐regulated in RASFs in the presence of proinflammatory cytokines. Absence of OPTN might worsen RA by generating a joint‐destructive state, as indicated by evidence of increased RANKL expression on RASFs and subsequent osteoclast differentiation.

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

“…Given the finding by a recent study that RANKL expressed on synovial fibroblast membrane plays an imperative role in bone erosions during joint inflammation [47], it is worth investigating how multiple cytokines act on those cells to express RANKL [48]. Our recent study has shown that IFN-c increases RANKL expression on synovial fibroblasts without affecting the levels of osteoprotegerin, an endogenous decoy receptor for RANKL [49]. From a more clinical point of view, recombinant IFN-c-1b is currently used to slow the progression of severe subtype of osteopetrosis, a genetic disorder associated with osteoclast dysfunction [50].…”

Clinical heterogeneity within the ALS‐FTD spectrum in a family with a homozygous optineurin mutation

“…7 Recently, OPTN has also attracted attention for its role as a modulator in autoimmune disorders. [42][43][44] In RA, OPTN was shown to play a protective role against joint destruction by downregulation of receptor activator of nuclear factor-jB ligand (RANKL). It was hypothesized that the absence of OPTN might worsen RA by the facilitation of a joint-destructive condition.…”

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

“…The expression of the autophagy receptor optineurin in FLS has been documented to be decreased under the action of a variety of inflammatory factors (e.g., TNF-a). Subsequently, it reportedly stimulates the expression of RANKL and the differentiation of osteoclasts (124). Kruppel-like factor 2 (KIF) negatively regulates the expression of the autophagy protein Beclin1 in monocytes and induces osteoclast differentiation and autophagy levels to enhance joint inflammation and bone destruction (125).…”