title: The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis.
abstract: ARS-interacting multifunctional protein 1 (AIMP1) induces production of inflammatory cytokines from immune cells. Since osteoclastogenesis is promoted by positive regulation of inflammatory cytokines, whether AIMP1 could promote osteoclastogenesis was investigated. AIMP1 induced osteoclastogenesis and acted synergistically with RANKL to promote osteoclastogenesis. Down-regulation of CD23, an AIMP1 receptor, abolished AIMP1-mediated osteoclastogenesis. Enzyme-linked immunosorbent assays showed that the AIMP1 level was significantly higher in the peripheral blood (PB) and synovial fluid of rheumatoid arthritis patients than in normal PB. A monoclonal antibody (clone 15B3AF) that blocked the cytokine activity of AIMP1 inhibited the AIMP1-mediated production of inflammatory cytokines. Clone 15B3AF inhibited the AIMP1-mediated osteoclastogenesis in vitro. We then cloned the complementary determining regions of clone 15B3AF and generated a chimeric antibody (atliximab). In a collagen-induced arthritis mouse model (CIA), atliximab administration significantly attenuated disease severity and improved various histopathological parameters. Three-dimensional micro-computed tomography scanning confirmed that atliximab enhanced the joint structures in CIA mice. Furthermore, atliximab decreased the expression of inflammatory cytokines in the serum and inflamed joints of CIA mice. Taken together, our findings suggest that AIMP1 exacerbates RA by promoting inflammation and osteoclastogenesis and that atliximab could be developed as a therapeutic antibody to target inflammatory diseases, including RA.
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyunggido, Republic of Korea.
authors.forename: Shin Hee
authors.initials: SH
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyunggido, Republic of Korea; Department of Biomedical Science, CHA University, Sungnamsi, Gyunggido 463-836, Republic of Korea.
authors.forename: Jin Gu
authors.initials: JG
authors.lastname: Cho
authors.affiliation: Department of Neurosurgery, St Peter's Kangnam Hospital, Seoul, Republic of Korea.
authors.forename: Kang Jun
authors.initials: KJ
authors.lastname: Yoon
authors.affiliation: Department of Applied Bioscience, CHA University, 222 Yatapdong, Bundanggu, Sungnamsi, Gyunggido 463836, Republic of Korea.
authors.forename: Dae-Seog
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, 134 Shinchon, Seodaemungu, Seoul 120-749, Republic of Korea.
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Yonsei University College of Medicine, 134 Shinchon, Seodaemungu, Seoul 120-749, Republic of Korea.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Gyunggido, Republic of Korea. Electronic address: sgpark@ajou.ac.kr.
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D055114:X-Ray Microtomography
chemical_list: C514492:Aimp1 protein, mouse; D000906:Antibodies; D057134:Antibodies, Neutralizing; D016207:Cytokines; D018836:Inflammation Mediators; D009363:Neoplasm Proteins; D053245:RANK Ligand; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C077219:small inducible cytokine subfamily E, member 1
keywords: AIMP1; Arthritis; Cytokine; Osteoclastogenesis