PMID- 32307918 OWN - NLM STAT- MEDLINE DCOM- 20210111 LR - 20210111 IS - 2326-5205 (Electronic) IS - 2326-5191 (Linking) VI - 72 IP - 9 DP - 2020 Sep TI - Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial Fibroblasts. PG - 1493-1504 LID - 10.1002/art.41290 [doi] AB - 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-gamma (IFNgamma), 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 IFNgamma treatment. OPTN-reduced RASFs were cocultured with monocytes and stained for tartrate-resistant acid phosphatase (TRAP). IkappaBalpha, NF-kappaB1, and RelA protein levels were measured to evaluate NF-kappaB 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 IFNgamma, 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). IkappaBalpha degradation and nuclear NF-kappaB1 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. CI - (c) 2020, American College of Rheumatology. FAU - Lee, Wen Shi AU - Lee WS AUID- ORCID: 0000-0002-6423-7264 AD - Hokkaido University, Sapporo, Japan, and Tokyo Medical and Dental University, Tokyo, Japan. FAU - Kato, Masaru AU - Kato M AUID- ORCID: 0000-0002-2023-6585 AD - Hokkaido University, Sapporo, Japan. FAU - Sugawara, Eri AU - Sugawara E AUID- ORCID: 0000-0003-2464-1833 AD - Hokkaido University, Sapporo, Japan. FAU - Kono, Michihiro AU - Kono M AUID- ORCID: 0000-0003-2245-943X AD - Hokkaido University, Sapporo, Japan. FAU - Kudo, Yuki AU - Kudo Y AD - Hokkaido University, Sapporo, Japan. FAU - Kono, Michihito AU - Kono M AUID- ORCID: 0000-0002-7663-534X AD - Hokkaido University, Sapporo, Japan. FAU - Fujieda, Yuichiro AU - Fujieda Y AUID- ORCID: 0000-0003-4705-341X AD - Hokkaido University, Sapporo, Japan. FAU - Bohgaki, Toshiyuki AU - Bohgaki T AD - Hokkaido University, Sapporo, Japan. FAU - Amengual, Olga AU - Amengual O AD - Hokkaido University, Sapporo, Japan. FAU - Oku, Kenji AU - Oku K AD - Hokkaido University, Sapporo, Japan. FAU - Yasuda, Shinsuke AU - Yasuda S AUID- ORCID: 0000-0001-6171-2077 AD - Hokkaido University, Sapporo, Japan, and Tokyo Medical and Dental University, Tokyo, Japan. FAU - Onodera, Tomohiro AU - Onodera T AD - Hokkaido University, Sapporo, Japan. FAU - Iwasaki, Norimasa AU - Iwasaki N AD - Hokkaido University, Sapporo, Japan. FAU - Atsumi, Tatsuya AU - Atsumi T AD - Hokkaido University, Sapporo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200803 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (CHST15 protein, human) RN - 0 (Cell Cycle Proteins) RN - 0 (GATA1 Transcription Factor) RN - 0 (GATA1 protein, human) RN - 0 (GATA3 Transcription Factor) RN - 0 (GATA3 protein, human) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (Membrane Glycoproteins) RN - 0 (Membrane Transport Proteins) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (NFKB1 protein, human) RN - 0 (OPTN protein, human) RN - 0 (Osteoprotegerin) RN - 0 (RANK Ligand) RN - 0 (RELA protein, human) RN - 0 (TNFRSF11B protein, human) RN - 0 (TNFSF11 protein, human) RN - 0 (Transcription Factor RelA) RN - 0 (Tumor Necrosis Factor-alpha) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.4.1.17 (HAS1 protein, human) RN - EC 2.4.1.212 (Hyaluronan Synthases) RN - EC 2.8.2.- (Sulfotransferases) RN - EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Arthritis, Rheumatoid/*genetics/metabolism MH - Blotting, Western MH - Cell Cycle Proteins/*genetics/metabolism MH - Cell Differentiation MH - Coculture Techniques MH - Fibroblasts/drug effects/*metabolism MH - GATA1 Transcription Factor/genetics MH - GATA3 Transcription Factor/genetics MH - Humans MH - Hyaluronan Synthases/genetics MH - Interferon-gamma/pharmacology MH - Interleukin-6/genetics MH - Matrix Metalloproteinase 3/genetics MH - Membrane Glycoproteins/genetics MH - Membrane Transport Proteins/*genetics/metabolism MH - Monocytes MH - NF-KappaB Inhibitor alpha/metabolism MH - NF-kappa B p50 Subunit/metabolism MH - Osteoprotegerin/metabolism MH - RANK Ligand/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Sulfotransferases/genetics MH - Synovial Membrane/*cytology MH - Tartrate-Resistant Acid Phosphatase/metabolism MH - Transcription Factor RelA/metabolism MH - Tumor Necrosis Factor-alpha/pharmacology EDAT- 2020/04/21 06:00 MHDA- 2021/01/12 06:00 CRDT- 2020/04/21 06:00 PHST- 2019/08/20 00:00 [received] PHST- 2020/04/14 00:00 [accepted] PHST- 2020/04/21 06:00 [pubmed] PHST- 2021/01/12 06:00 [medline] PHST- 2020/04/21 06:00 [entrez] AID - 10.1002/art.41290 [doi] PST - ppublish SO - Arthritis Rheumatol. 2020 Sep;72(9):1493-1504. doi: 10.1002/art.41290. Epub 2020 Aug 3.