TITLE:
Iguratimod, a Disease-Modifying Anti-Rheumatic Drug, Inhibits Osteoclastogenesis and Bone Resorption through Suppression of the Nuclear Factor of Activated T Cells Signaling Pathway
AUTHORS:
Jun Shiota, Hidetoshi Murao, Akihiko Miura, Masaaki Mikami, Keiichi Tanaka
KEYWORDS:
Bone Resorption, Iguratimod, NFATc1, Osteoclast, Rheumatoid Arthritis
JOURNAL NAME:
Open Journal of Rheumatology and Autoimmune Diseases,
Vol.6 No.4,
November
21,
2016
ABSTRACT: 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.