Dataset Information

Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra-induced bone loss by modulating RANKL signaling pathways.

ABSTRACT: Receptor activator of NF-?B ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-?B activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways.

SUBMITTER: Li X

PROVIDER: S-EPMC3774760 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra-induced bone loss by modulating RANKL signaling pathways.

Li Xiaojuan X He Longgang L Hu Yiping Y Duan Heng H Li Xianglian X Tan Suiyi S Zou Min M Gu Chunping C Zeng Xiangzhou X Yu Le L Xu Jiake J Liu Shuwen S

PloS one 20130916 9

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rat ...[more]

PMID: 24066131

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Project description:Excessive osteoclast-mediated bone resorption is a critical cause of osteoporosis affecting many aging people worldwide. 5'-Methylthioadenosine (MTA) is a natural sulfur-containing nucleoside normally produced in prokaryotes, plants, yeast, and higher eukaryotes via polyamine metabolism. MTA affects various physiological responses particularly the inflammatory pathway in both normal and cancerous cells and modulates the activation of nuclear factor-κB involved in the osteoclastogenesis signalling process. While several studies have reported that natural products possess anti-osteoclastogenesis phenolics and flavonoids, the effect of nucleoside derivatives on osteoclastogenesis remains limited. Therefore, this study aimed to explore the molecular mechanisms by which MTA affects pre-osteoclastic RAW 264.7 cells as a potential alleviation compound for inflammation-mediated bone loss. Osteoclasts were established by incubating RAW264.7 macrophage cells with receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor, the vital cytokines for activation of osteoclast differentiation. Cell viability was measured using MTT assays at 24, 48, and 72 h. The suppressive effect of MTA on RANKL-induced osteoclast differentiation and function was assessed using tartrate-resistant acid phosphatase (TRAP) analysis, qRT-PCR, and pit formation, Western blot, and immunofluorescence assays. MTA showed dose-dependent anti-osteoclastogenic activity by inhibiting TRAP-positive cell and pit formation and reducing essential digestive enzymes, including TRAP, cathepsin K, and matrix metallopeptidase 9. MTA was observed to suppress the osteoclast transduction pathway through (RANKL)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NFƘB); it attenuated NFƘB-P65 expression and down-regulated cFos proto-oncogene and nuclear factor of activated T cell c1 (NFATc1), the main regulators of osteoclasts. Moreover, the suppression of RANK (the initial receptor triggering several osteoclastogenic transduction pathways) was observed. Thus, this study highlights the potential of MTA as an effective therapeutic compound for restoring bone metabolic disease by inhibiting the RANK-NFATc1 signal pathway.

Dataset Information

Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra-induced bone loss by modulating RANKL signaling pathways.

Publications

Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra-induced bone loss by modulating RANKL signaling pathways.

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