Author(s)

Jun Shiota, Hidetoshi Murao, Akihiko Miura, Masaaki Mikami, Keiichi Tanaka^*

Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan.

Introduction: The aim of this study was to observe an inhibition of bone resorption and osteoclastogenesis by iguratimod (IGU, T-614), a disease-modifying anti-rheumatic drug, using adjuvant-induced arthritis (AIA) rats and receptor activator of nuclear factor kappa-B ligand (RANKL)-stimulated RAW264.7 cells. Methods: The bone mineral density and 3D morphometric parameters of hind paws in AIA rats were measured using micro computed tomography (μCT) imaging. The activity of osteoclast cells was estimated based on tartrate-resistant acid phosphatase (TRAP) staining in specimens from the rats. In vitro TRAP activity was investigated using RANKL-stimulated RAW264.7 cells. The amount of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) protein was measured by western blot analysis. The expression of Nfatc1, its regulator genes, its upstream factors, and osteoclast-functional genes were investigated. Results: In addition to the suppression of bone resorption and lesions of bone trabeculae of AIA rats, IGU significantly decreased the number of TRAP-positive cells in the calcaneal bones. Moreover, this drug inhibited the differentiation of RANKL-stimulated RAW264.7 cells into osteoclasts, which were identified morphologically and functionally. IGU decreased the amount of NFATc1 protein and improved the altered expression of NFATc1-associated genes and osteoclast-functional genes. Conclusions: IGU suppressed osteoclastogenesis and bone resorption via the RANKL-NFATc1 pathway, suggesting such effect would be expected in clinical use.

Bone Resorption, Iguratimod, NFATc1, Osteoclast, Rheumatoid Arthritis

Shiota, J. , Murao, H. , Miura, A. , Mikami, M. and Tanaka, K. (2016) Iguratimod, a Disease-Modifying Anti-Rheumatic Drug, Inhibits Osteoclastogenesis and Bone Resorption through Suppression of the Nuclear Factor of Activated T Cells Signaling Pathway. Open Journal of Rheumatology and Autoimmune Diseases, 6, 106-119. doi: 10.4236/ojra.2016.64017.