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Int Immunopharmacol ; 58: 136-144, 2018 May.
Article in English | MEDLINE | ID: mdl-29587202

ABSTRACT

Tofacitinib, a small molecule JAK inhibitor, has been widely used to reduce inflammation and inhibit progression of bone destruction in rheumatoid arthritis. STAT3, a downstream signaling molecule of JAK, plays a key role in the activation of signaling in response to inflammatory cytokines. Thus, targeting STAT3 may be an inspiring strategy for treating osteoclast-related diseases such as rheumatoid arthritis. In this study, we first investigated the effects of Stattic, a STAT3 inhibitor, on receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis. Stattic inhibited osteoclast differentiation and bone resorption in RANKL-induced RAW264.7 cells in a dose-dependent manner. Stattic also suppressed RANKL-induced upregulation of osteoclast-related genes tartrate-resistant acid phosphatase, matrix metalloproteinase 9, cathepsin K, RANK, tumor necrosis factor receptor-associated factor 6, and osteoclast-associated receptor in RAW264.7 cells. Moreover, Stattic exhibited an inhibitory effect on cell proliferation and cell cycle progression at higher dosages. At the molecular level, Stattic inhibited RANKL-induced activation of STAT3 and NF-κB pathways, without significantly affecting MAPK signaling. In addition, Stattic inhibited RANKL-induced expression of osteoclast-related transcription factors c-Fos and NFATc1. Importantly, Stattic also prevented bone loss caused by ovariectomy. Together, our data confirm that Stattic restricts osteoclastogenesis and bone loss by disturbing RANKL-induced STAT3 and NF-κB signaling. Thus, Stattic represents a novel type of osteoclast inhibitor that could be useful for conditions such as osteoporosis and rheumatoid arthritis.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Bone Resorption/drug therapy , Cyclic S-Oxides/pharmacology , Macrophages/drug effects , Osteogenesis/drug effects , STAT3 Transcription Factor/metabolism , Animals , Gene Expression Regulation , Genes, fos/genetics , Humans , Janus Kinases/antagonists & inhibitors , Macrophages/physiology , Mice , NF-kappa B/metabolism , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Osteogenesis/genetics , Piperidines/pharmacology , Piperidines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Pyrroles/pharmacology , Pyrroles/therapeutic use , RANK Ligand/metabolism , RAW 264.7 Cells , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction
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