Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-κB pathways
| Autor: | Lin Sun, Jinxia Zhao, Xiangyuan Liu, Lin-lin Xu, Ruohan Yu, Changhong Li, Leilei Jian, Guo-hong Du |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine STAT3 Transcription Factor Immunology Proinflammatory cytokine Arthritis Rheumatoid 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Piperidines Osteoclast Osteogenesis medicine Immunology and Allergy Animals Humans Pyrroles Bone Resorption STAT3 Janus Kinases Pharmacology biology NFATC Transcription Factors Macrophages RANK Ligand NF-kappa B Genes fos NF-κB Cyclic S-Oxides 030104 developmental biology medicine.anatomical_structure Pyrimidines RAW 264.7 Cells chemistry Gene Expression Regulation RANKL 030220 oncology & carcinogenesis Cancer research biology.protein Tumor necrosis factor alpha Signal transduction Janus kinase Signal Transduction |
| Zdroj: | International immunopharmacology. 58 |
| ISSN: | 1878-1705 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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