title: Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy.
abstract: Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvβ3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.
authors: Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China 322100; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40466;
authors: Chen-Ming
authors: CM
authors: Su
authors: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40466;
authors: Yi-Chun
authors: YC
authors: Chiang
authors: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 40466; Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan 65142;
authors: Chun-Yin
authors: CY
authors: Huang
authors: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan 40466; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan 40466;
authors: Chin-Jung
authors: CJ
authors: Hsu
authors: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan 40466; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan 40466;
authors: Yi-Chin
authors: YC
authors: Fong
authors: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40466; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan 40466; and Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan 40466 chtang@mail.cmu.edu.tw.
authors: Chih-Hsin
authors: CH
authors: Tang
mesh_terms: D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000628:therapy; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053683:Oncostatin M / Q000096:biosynthesis* / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; C508351:OSM protein, human; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D053495:Osteopontin; D053683:Oncostatin M; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases