Akira Miyama1, Kosuke Ebina2, Makoto Hirao1, Gensuke Okamura3, Yuki Etani1, Kenji Takami1, Atsushi Goshima1, Taihei Miura1, Shohei Oyama4, Takashi Kanamoto5, Hideki Yoshikawa6, Ken Nakata5. 1. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. 2. Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. k-ebina@umin.ac.jp. 3. Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Kita-ku, Sakai, 591-8025, Japan. 4. Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. 5. Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. 6. Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka, 560-8565, Japan.
Abstract
INTRODUCTION: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. MATERIALS AND METHODS: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. RESULTS: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. CONCLUSION: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.
INTRODUCTION: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. MATERIALS AND METHODS: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. RESULTS: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. CONCLUSION: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.
Authors: Lenore Buckley; Gordon Guyatt; Howard A Fink; Michael Cannon; Jennifer Grossman; Karen E Hansen; Mary Beth Humphrey; Nancy E Lane; Marina Magrey; Marc Miller; Lake Morrison; Madhumathi Rao; Angela Byun Robinson; Sumona Saha; Susan Wolver; Raveendhara R Bannuru; Elizaveta Vaysbrot; Mikala Osani; Marat Turgunbaev; Amy S Miller; Timothy McAlindon Journal: Arthritis Rheumatol Date: 2017-06-06 Impact factor: 10.995
Authors: Josef S Smolen; Robert Landewé; Johannes Bijlsma; Gerd Burmester; Katerina Chatzidionysiou; Maxime Dougados; Jackie Nam; Sofia Ramiro; Marieke Voshaar; Ronald van Vollenhoven; Daniel Aletaha; Martin Aringer; Maarten Boers; Chris D Buckley; Frank Buttgereit; Vivian Bykerk; Mario Cardiel; Bernard Combe; Maurizio Cutolo; Yvonne van Eijk-Hustings; Paul Emery; Axel Finckh; Cem Gabay; Juan Gomez-Reino; Laure Gossec; Jacques-Eric Gottenberg; Johanna M W Hazes; Tom Huizinga; Meghna Jani; Dmitry Karateev; Marios Kouloumas; Tore Kvien; Zhanguo Li; Xavier Mariette; Iain McInnes; Eduardo Mysler; Peter Nash; Karel Pavelka; Gyula Poór; Christophe Richez; Piet van Riel; Andrea Rubbert-Roth; Kenneth Saag; Jose da Silva; Tanja Stamm; Tsutomu Takeuchi; René Westhovens; Maarten de Wit; Désirée van der Heijde Journal: Ann Rheum Dis Date: 2017-03-06 Impact factor: 19.103