title: Role of S100A12 in the pathogenesis of osteoarthritis.
abstract: S100A12 is a member of the S100 protein family, which are intracellular calcium-binding proteins. Although there are many reports on the involvement of S100A12 in inflammatory diseases, its presence in osteoarthritic cartilage has not been reported. The purpose of this study was to investigate the expression of S100A12 in human articular cartilage in osteoarthritis (OA) and to evaluate the role of S100A12 in human OA chondrocytes. We analyzed S100A12 expression by immunohistochemical staining of cartilage samples obtained from OA and non-OA patients. In addition, chondrocytes were isolated from knee cartilage of OA patients and treated with recombinant human S100A12. Real-time RT-PCR was performed to analyze mRNA expression. Protein production of matrix metalloproteinase 13 (MMP-13) and vascular endothelial growth factor (VEGF) in the culture medium were measured by ELISA. Immunohistochemical analyses revealed that S100A12 expression was markedly increased in OA cartilages. Protein production and mRNA expression of MMP-13 and VEGF in cultured OA chondrocytes were significantly increased by treatment with exogenous S100A12. These increases in mRNA expression and protein production were suppressed by administration of soluble receptor for advanced glycation end products (RAGE). Both p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) inhibitors also suppressed the increases in mRNA expression and protein production of MMP-13 and VEGF. We demonstrated marked up-regulation of S100A12 expression in human OA cartilages. Exogenous S100A12 increased the production of MMP-13 and VEGF in human OA chondrocytes. Our data indicate the possible involvement of S100A12 in the development of OA by up-regulating MMP-13 and VEGF via p38 MAPK and NF-κB pathways.
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Motoshige
authors.initials: M
authors.lastname: Nakashima
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sakai
authors.forename: Hideki
authors.initials: H
authors.lastname: Hiraiwa
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Takaaki
authors.initials: T
authors.lastname: Omachi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ono
authors.forename: Norio
authors.initials: N
authors.lastname: Inukai
authors.forename: Shinya
authors.initials: S
authors.lastname: Ishizuka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oda
authors.forename: Akira
authors.initials: A
authors.lastname: Takamatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
mesh_terms: D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D009418:S100 Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D000067616:S100A12 Protein; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13