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Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-?B signaling pathways via selective estrogen receptor ?.

ABSTRACT: Bu-Shen-Ning-Xin decoction (BSNXD) is a traditional Chinese medicinal composition that has been used as a remedy for postmenopausal osteoporosis, but the mechanisms affecting bone metabolism are not fully understood.We investigated the molecular mechanism and signaling pathway underlying the effect of BSNXD on osteoclastogenesis.A postmenopausal osteoporosis animal model generated by ovariectomy was administered BSNXD and drug-derived serum was prepared. An enzyme immunoassay was conducted to measure the 17-?-estradiol (E2) concentration in the drug-derived serum. Bone marrow-derived monocyte/macrophage precursor cells were treated with drug-derived serum, and tartrate-resistance acid phosphatase staining was conducted to observe osteoclastogenesis. A bone resorption assay was performed to analyze the effect on osteoclastic resorptive function. Real-time PCR, flow cytometry, Western blotting, transfection, and luciferase assays were conducted to explore the related mechanism.E2 was not elevated in BSNXD-derived serum. BSNXD-derived serum suppressed receptor activation of nuclear factor ?B ligand (RANKL)-activated osteoclastogenesis in a dose-dependent manner; this effect could be reversed by estrogen receptor ? antagonist methyl-piperidino-pyrazole. The serum suppressed RANKL-induced NF-?B transcription and inhibited the accumulation of nuclear factor of activated T-cells, cytoplasmic 1 in osteoclast precursor cells; the inhibitory effect was abolished by methyl-piperidino-pyrazole but not the estrogen receptor ? antagonist or androgen receptor antagonist.These results collectively suggest that administration of BSNXD presents inhibitory effects on osteoclast differentiation by abrogating the RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1 and NF-?B signaling pathways downstream of estrogen receptor ?, thereby contributing to the inhibitory effect on bone resorption.

SUBMITTER: Wang L

PROVIDER: S-EPMC4516212 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-κB signaling pathways via selective estrogen receptor α.

Wang Ling L Qiu Xue-Min XM Gui Yu-Yan YY Xu Ying-Ping YP Gober Hans-Jürgen HJ Li Da-Jin DJ

Drug design, development and therapy 20150721

<h4>Introduction</h4>Bu-Shen-Ning-Xin decoction (BSNXD) is a traditional Chinese medicinal composition that has been used as a remedy for postmenopausal osteoporosis, but the mechanisms affecting bone metabolism are not fully understood.<h4>Purpose</h4>We investigated the molecular mechanism and signaling pathway underlying the effect of BSNXD on osteoclastogenesis.<h4>Materials and methods</h4>A postmenopausal osteoporosis animal model generated by ovariectomy was administered BSNXD and drug-de ...[more]

PMID: 26229438

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Project description:Postmenopausal osteoporosis (PMO) has been recognized as an inflammatory condition. CD4+ T cells serve a key role in the interaction between bone metabolism and the immune system. Bu‑Shen‑Ning‑Xin decoction (BSNXD), a traditional Chinese medicine, has been ultilized as a remedy for PMO. In the present study, the aim was to investigate the immune modulatory effects of BSNXD on CD4+ T cells, receptor activation of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) imbalance, skeletal parameters and osteoclastogenesis. Ovariectomized (OVX) mice were treated with a series of concentrations of BSNXD and then autopsied. The bone phenotype was analyzed by micro computed tomography. CD4+ T cells were isolated and their percentage was measured using flow cytometry (FCM). RANKL and OPG expression by the CD4+ T cells at the transcriptional and translational levels were quantified by reverse transcription-quantitative polymerase chain reaction, ELISA and FCM. CD4+ T cells were cultured with blood serum derived from BSNXD‑treated OVX mice (BSNXD‑derived serum) and the apoptosis rate was quantified by FCM. CD4+ T cells were co-cultured with bone marrow‑derived macrophages and exposed to BSNXD‑derived serum to whether CD4+ T cells are involved in BSNXD‑modulated osteoclastogenesis and the results were quantified via tartrate‑resistant acid phosphatase staining. The results revealed that BSNXD ameliorated OVX‑induced bone loss, prevented the expansion of CD4+ T cells and restored the RANKL/OPG imbalance in the CD4+ T cells of OVX mice. In vitro, BSNXD‑derived serum promoted the apoptosis of CD4+ T cells. The co‑culture system demonstrated that CD4+ T cells from OVX mice increase osteoclastogenesis, while this effect was suppressed by BSNXD administration. The findings of the study collectively suggest that BSNXD exerts an immunoprotective effect on the bone phenotype of OVX mice by ameliorating RANKL/OPG imbalance in CD4+ T cells and attenuating osteoclastogenesis.

Project description:TNF induces bone loss in common bone diseases by promoting osteoclast formation directly and indirectly, but it also limits osteoclast formation by inducing expression of NF-κB p100. Osteoclast precursors (OCPs) are derived from M1 (inflammatory) and M2 (resident) macrophages. However, it is not known if TNF stimulates or limits osteoclast formation through regulation of M1 or M2 differentiation or if RelB, a partner of p100, is involved. To investigate these questions, we treated bone marrow cells (BMCs) with M-CSF alone or in combination with TNF to enrich for OCPs, which we called M-OCPs and T-OCPs, respectively. We found that TNF switched CD11b+F4/80+ M-OCPs from Ly6C-Gr1- M2 to Ly6C+Gr1-CD11c+ and Ly6C-Gr1-CD11c+ M1 cells. RANKL induced osteoclast formation from both Ly6C+Gr1- and Ly6C-Gr1- T-OCPs, but only from Ly6C+Gr1- M-OCPs, which formed significantly fewer osteoclasts than T-OCPs. Importantly, Ly6C+Gr1- cells from both M- and T-OCPs have increased expression of the M1 marker genes, iNOS, TNF, IL-1β and TGFβ1, compared to Ly6C-Gr1- cells, and Ly6C-Gr1- cells from T-OCPs also have increased expression of iNOS and TGFβ1 compared to cells from M-OCPs. Both RANKL and TNF increased RelB mRNA expression. TNF significantly increased RelB protein levels, but RANKL did not because it also induced RelB proteasomal degradation. TNF inhibited RANKL-induced NFATc1 mRNA expression and osteoclast formation from M-OCPs, but not from T-OCPs, and it did not induce Ly6C+Gr1-CD11c+ or Ly6C-Gr1-CD11c+ M1 macrophages from RelB-/- BMCs. Furthermore, overexpression of RelB in M-OCPs reduced RANKL-induced osteoclast formation and NFATc1 mRNA expression, but it increased TNF-induced OC formation without affecting NFATc1 levels. Thus, TNF induction of RelB directly mediates terminal osteoclast differentiation independent of NFATc1 and limits RANKL-induced osteoclastogenesis by inhibiting NFATc1 activation. However, the dominant role of TNF is to expand the OCP pool by switching the differentiation of M-CSF-induced M2 to M1 macrophages with enhanced osteoclast forming potential. Strategies to degrade RelB could prevent TNF-induced M2/M1 switching and reduce osteoclast formation.

Dataset Information

Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-?B signaling pathways via selective estrogen receptor ?.

Publications

Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-κB signaling pathways via selective estrogen receptor α.

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