Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro

• Published in: Journal of bone and mineral metabolism 2021-07, Vol.39 (4), p.639-648
• Main Authors: Miyama, Akira, Ebina, Kosuke, Hirao, Makoto, Okamura, Gensuke, Etani, Yuki, Takami, Kenji, Goshima, Atsushi, Miura, Taihei, Oyama, Shohei, Kanamoto, Takashi, Yoshikawa, Hideki, Nakata, Ken
• Format: Article
• Language: English
• Subjects: Acid phosphatase (tartrate-resistant); Alkaline phosphatase; Alkaline Phosphatase - genetics; Alkaline Phosphatase - metabolism; Animals; Arthritis, Rheumatoid - drug therapy; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Bone resorption; Bone Resorption - pathology; Bone turnover; Calcification, Physiologic - drug effects; Cell Count; Cell Line; Chromones - pharmacology; Chromones - therapeutic use; Dexamethasone; Down-Regulation - drug effects; Gene expression; Glucocorticoids; Glucocorticoids - adverse effects; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mineralization; NF-κB protein; Original Article; Orthopedics; Osteoblastogenesis; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteocalcin; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; Osteoporosis; Osteoprotegerin; Phosphatase; Polymerase chain reaction; Rheumatoid arthritis; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TRAF6 protein; TRANCE protein; Tumor necrosis factor receptors; Up-Regulation - drug effects; Western blotting
• ISSN: 0914-8779; 1435-5604; 1435-5604
• DOI: 10.1007/s00774-021-01206-5

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.