Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial Fibroblasts
- 1 September 2020
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatology
- Vol. 72 (9), 1493-1504
- https://doi.org/10.1002/art.41290
Abstract
Objective Optineurin (OPTN) is an autophagy adaptor/receptor that acts as an intrinsic negative regulator of osteoclast differentiation.RANKLexpressed by rheumatoid arthritis synovial fibroblasts (RASFs) is primarily responsible for the development of bone erosions in patients withRA. The aim of the present study was to explore the role ofOPTNin the pathogenesis of joint destruction inRA. Methods RASFs were left untreated or incubated with tumor necrosis factor (TNF) or interferon-gamma (IFN gamma), and expression ofOPTNbyRASFs was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Expression ofRANKLand osteoprotegerin (OPG) was evaluated in cultures ofOPTN-reducedRASFs with or withoutTNForIFN gamma treatment.OPTN-reducedRASFs were cocultured with monocytes and stained for tartrate-resistant acid phosphatase (TRAP). I kappa B alpha,NF-kappa B1, and RelA protein levels were measured to evaluateNF-kappa B signaling. Expression of messengerRNA(mRNA) for matrix metalloproteinase 3 (MMP3), interleukin-6 (IL6),GATAbinding protein 3 (GATA3), carbohydrate sulfotransferase 15 (CHST15), hyaluronan synthase 1 (HAS1), andGATA1was analyzed byRT-qPCR. Results InRASFs incubated withTNForIFN gamma,OPTNexpression was up-regulated andRANKLexpression was increased, and these effects were further pronounced inOPTN-reducedRASFs (allP< 0.05 versus controls).OPG mRNAlevels remained unchanged. Monocytes cocultured withOPTN-reducedRASFs differentiated to a greater extent intoTRAP+ multinucleated cells compared to monocytes cocultured with controlRASFs (P< 0.05). I kappa B alpha degradation and nuclearNF-kappa B1 expression followingTNFtreatment were both prolonged inOPTN-reducedRASFs (eachP< 0.05 versus controls).MMP3mRNAlevels were up-regulated, whileGATA3,CHST15, andHAS1mRNAlevels were down-regulated inOPTN-reducedRASFs (eachP< 0.05 versus controls). Conclusion OPTNplays a protective role inRAwhen it is up-regulated inRASFs in the presence of proinflammatory cytokines. Absence ofOPTNmight worsenRAby generating a joint-destructive state, as indicated by evidence of increasedRANKLexpression onRASFs and subsequent osteoclast differentiation.Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (16K19591)
This publication has 50 references indexed in Scilit:
- The role of RANK ligand/osteoprotegerin in rheumatoid arthritisTherapeutic Advances in Musculoskeletal Disease, 2012
- Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritisArthritis Research & Therapy, 2011
- The Roles of Interleukin-6 in the Pathogenesis of Rheumatoid ArthritisArthritis, 2011
- Optineurin in neurodegenerative diseasesNeuropathology, 2011
- Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytesArthritis Research & Therapy, 2010
- NF-κB Mediates Tumor Necrosis Factor α-Induced Expression of Optineurin, a Negative Regulator of NF-κBPLOS ONE, 2009
- GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiationNature Reviews Immunology, 2009
- Functions of RANKL/RANK/OPG in bone modeling and remodelingArchives of Biochemistry and Biophysics, 2008
- Cytokines in the pathogenesis of rheumatoid arthritisNature Reviews Immunology, 2007
- Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblastsArthritis & Rheumatism, 2004