PMID- 32131874 OWN - NLM STAT- MEDLINE DCOM- 20201218 LR - 20201218 IS - 1749-799X (Electronic) IS - 1749-799X (Linking) VI - 15 IP - 1 DP - 2020 Mar 4 TI - The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3. PG - 87 LID - 10.1186/s13018-020-01595-9 [doi] LID - 87 AB - BACKGROUND AND AIM: The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management. METHODS: We investigated the effect of administering a low dose (1000 muM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived 2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS). RESULTS: Low-dose NAC (1000 muM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 muM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 muM) to RA-FLS suppressed MMP-3. CONCLUSIONS: We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies. FAU - Kanai, Tomotake AU - Kanai T AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. FAU - Kondo, Naoki AU - Kondo N AUID- ORCID: 0000-0002-8985-3055 AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. naokikondo1214@gmail.com. FAU - Okada, Masayasu AU - Okada M AD - Department of Neurosurgery, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Niigata, Japan. FAU - Sano, Hiroshige AU - Sano H AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. FAU - Okumura, Go AU - Okumura G AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. FAU - Kijima, Yasufumi AU - Kijima Y AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. FAU - Ogose, Akira AU - Ogose A AD - Department of Orthopedic Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minami-Uonuma, Niigata, Japan. FAU - Kawashima, Hiroyuki AU - Kawashima H AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. FAU - Endo, Naoto AU - Endo N AD - Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan. LA - eng GR - 18K09057/Ministry of Education, Culture, Sports, Science and Technology/ GR - 18K09098/Ministry of Education, Culture, Sports, Science and Technology/ GR - 17K10960/Ministry of Education, Culture, Sports, Science and Technology/ GR - 17K17739/Ministry of Education, Culture, Sports, Science and Technology/ PT - Journal Article DEP - 20200304 PL - England TA - J Orthop Surg Res JT - Journal of orthopaedic surgery and research JID - 101265112 RN - 0 (Antioxidants) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/administration & dosage MH - Adult MH - Aged, 80 and over MH - Antioxidants/*administration & dosage MH - Arthritis, Rheumatoid/drug therapy/*enzymology/pathology MH - Cell Survival/drug effects/physiology MH - Cells, Cultured MH - Drug Delivery Systems/*methods MH - Female MH - Humans MH - MAP Kinase Signaling System/drug effects/*physiology MH - Matrix Metalloproteinase 3/*metabolism MH - Middle Aged MH - Synoviocytes/drug effects/enzymology MH - Treatment Outcome PMC - PMC7371465 OTO - NOTNLM OT - JNK pathway OT - Low-dose NAC OT - MH7A OT - MMP-3 OT - RA-FLS COIS- The authors declare that they have no competing interest. EDAT- 2020/03/07 06:00 MHDA- 2020/12/19 06:00 PMCR- 2020/07/17 CRDT- 2020/03/06 06:00 PHST- 2019/11/06 00:00 [received] PHST- 2020/02/13 00:00 [accepted] PHST- 2020/03/06 06:00 [entrez] PHST- 2020/03/07 06:00 [pubmed] PHST- 2020/12/19 06:00 [medline] PHST- 2020/07/17 00:00 [pmc-release] AID - 10.1186/s13018-020-01595-9 [pii] AID - 1595 [pii] AID - 10.1186/s13018-020-01595-9 [doi] PST - epublish SO - J Orthop Surg Res. 2020 Mar 4;15(1):87. doi: 10.1186/s13018-020-01595-9.