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High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio.

ABSTRACT: The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, administration of EV or DG-H inhibited OVX-induced weight gain, and administration of EV or DG-H or DG-M had a significantly uterotrophic effect. Bone mineral density (BMD) and indices of bone histomorphometry of tibia were measured. Levels of protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibia were evaluated by immunohistochemistry and in situ hybridization. Our results show that DG at a high dose (DG-H) had a significant anti-osteoporotic effect compared to OVX control. DG-H treatment down-regulated expression of RANKL and up-regulated expression of OPG significantly in tibia from OVX rats compared to control, and thus lowered the RANKL/OPG ratio. This suggests that the anti-osteoporotic effect of DG might be associated with modulating the RANKL/OPG ratio and DG had potential to be developed as alternative therapeutic agents of osteoporosis induced by postmenopause.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC4200779 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio.

Zhang Zhiguo Z Song Changheng C Fu Xiaowei X Liu Meijie M Li Yan Y Pan Jinghua J Liu Hong H Wang Shaojun S Xiang Lihua L Xiao Gary Guishan GG Ju Dahong D

International journal of molecular sciences 20140925 9

The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, a ...[more]

PMID: 25257532

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Project description:The present study aimed to assess the changes in circulating microRNA (miRNA) expression profiles associated with the potential osteoprotective effect of diosgenin (DIO) in ovariectomized (OVX) rats. Wistar rats (female) were subjected to a sham operation (SHAM group) or ovariectomy. OVX rats were treated with DIO (DIO group) or vehicle (OVX group) for 12 weeks. Following treatment, the serum estradiol, bone turnover biomarker levels, and the microarchitecture of tibias were assayed. Based on miRNA microarray and qRT-PCR analyses, differentially expressed (DE) circulating miRNAs were identified between the OVX and SHAM groups (comparison A) and between the DIO and OVX groups (comparison B). Furthermore, putative target genes of shared DE miRNAs with opposite expression trends in the two comparisons were predicted by ingenuity pathway analysis (IPA). Finally, the expression levels of the putative target genes in serum and tibia were validated by qRT-PCR. The micro-CT results demonstrated that DIO had a substantial anti-osteopenic effect on the tibias of OVX rats. In total, we found 5 DE circulating miRNAs (four upregulated and one downregulated) in comparison A and 21 DE circulating miRNAs (15 upregulated and 6 downregulated) in comparison B. However, only one DE circulating miRNA (rno-miR-20a-5p) had opposite expression trends between the two comparisons. Including rno-miR-20a-5p, 7 of the 10 selected DE circulating miRNAs between the two comparisons passed qRT-PCR validation. Specifically, based on qRT-PCR validation, DIO upregulated the expression of rno-miR-20a-5p and downregulated that of three target genes (Tnf, Creb1, and Tgfbr2) of the "osteoclast differentiation" pathway in the tibias of OVX rats. Our results suggested that DIO could change the circulating miRNA profile of OVX rats and inhibited the downregulation of miR-20a-5p in serum and tibia. DIO might exert an anti-osteoclastogenic effect on OVX rats by upregulating the expression of miR-20a-5p in circulation and bone tissue.

Project description:Rheumatoid arthritis (RA) is closely associated with periarticular osteopenia and leads to a high risk of generalized osteoporosis. Although glucocorticoid (GC) treatment ameliorates joint degradation and manages inflammation in RA, GC application may induce further bone quality deterioration in RA patients. Current treatments for RA lack relevant strategies for the prevention and treatment of osteopenia in RA. In this study, we aimed to investigate whether salvianolate treatment ameliorated osteopenia in prednisone-treated RA rats. Lewis rats with collagen-induced arthritis (CIA) were administered prednisone (PDN) or PDN plus salvianolate (PDN+Sal) treatment for 90 days. The effects of Sal were investigated in PDN-treated CIA rats. To further evaluate the effects of Sal under inflammatory conditions, we investigated the effects of Sal treatment on the TNF-α-induced inflammatory response in MC3T3-E1 osteoblasts. Bone histomorphometry, bone mineral density (BMD), bone biomechanical properties, micro-computed tomography (micro-CT), immunohistochemistry, RT-PCR and western blot analyses were performed to evaluate the effects of Sal. The results demonstrated that RA induced bone loss and bone quality deterioration, with high bone turnover in CIA rats. PDN+Sal treatment significantly increased BMD and trabecular/cortical bone mass, suppressed inflammation, and improved bone biomechanical properties compared to CIA control and PDN treatment. PDN+Sal treatment significantly suppressed bone resorption and the RANKL and RANKL/OPG ratios compared to PDN. PDN+Sal and PDN treatment significantly inhibited TNF-α by 82 and 83%, respectively, and both suppressed inflammation in CIA rats. However, there was no significant difference between PDN+Sal and PDN treatment alone in regard to bone formation parameters or the management of inflammation and arthropathy. Sal significantly increased Osterix, OPN, and Col1a1 while decreasing RANKL, TRAF6, and TRAIL gene in TNF-α-induced MC3T3-E1 osteoblasts. Sal significantly increased Osterix, OPN and RUNX2 while decreasing NF-κB, TRAF6 and IL-1β protein in TNF-α-induced MC3T3-E1 osteoblasts. The results suggested that salvianolate treatment ameliorated osteopenia and improved bone quality in prednisone-treated RA rats, and the potential mechanism may be related to the regulation of the RANKL/RANK/OPG signaling pathway, TRAIL-TRAF6-NFκB signal axis, and downregulation of inflammatory cytokines. Salvianolate could be used as a promising supplemental therapeutic strategy to ameliorate osteopenia and improve bone quality in GC-treated RA patients.

Project description:BackgroundThe present study aimed to assess the perturbation in circular RNA (circRNA)/mRNA expression profiles and a circRNA-miRNA-mRNA coexpression network involved in the potential protective effect of diosgenin (DIO) on alveolar bone loss in rats subjected to ovariectomy (OVX).MethodsThe Wistar rats (female) manipulated with sham operation were classified as the SHAM group and the grouping of OVX rats administered with DIO, estradiol valerate or vehicle for 12 weeks was DIO group, EV group and OVX group respectively. Following treatments, the plasmatic levels of osteocalcin and tumor necrosis factor-alpha and the microstructure of alveolar bone were assayed. Based on microarray analyses, we identified differentially expressed (DE) circRNAs and mRNAs in alveolar bone of rats in both OVX and DIO group. The DE circRNAs and DE mRNAs involved in the bone metabolism pathway validated by RT-qPCR were considered key circRNAs/mRNAs. On the basis of these key circRNAs/mRNAs, we predicted the overlapping relative miRNAs of key circRNAs/mRNAs, and a circRNA-miRNA-mRNA network was built.ResultsDIO showed an anti-osteopenic effect on the rat alveolar bone loss induced by OVX. In total, we found 10 DE circRNAs (6 downregulated and 4 upregulated) and 614 DE mRNAs (314 downregulated and 300 upregulated) in samples of the DIO group compared with those of the OVX group. However, only one circRNA (rno_circRNA_016717) and seven mRNAs (Sfrp1, Csf1, Il1rl1, Nfatc4, Tnfrsf1a, Pik3c2g, and Wnt9b) were validated by qRT-PCR and therefore considered key circRNA/mRNAs. According to these key circRNA/mRNAs and overlapping predicted miRNAs, a coexpression network was constructed. After network analysis, one circRNA-miRNA-mRNA axis (circRNA_016717/miR-501-5p/Sfrp1) was identified.ConclusionThe mechanism of DIO inhibiting alveolar bone loss after OVX is possibly relevant to the simultaneous inhibition of osteogenesis and osteoclastogenesis by mediating the expression of important molecules in the Wnt, PI3K, RANK/RANKL or osteoclastogenic cytokine pathways. The circRNA_016717/miR-501-5p/Sfrp1 axis may play important roles in these processes.

Dataset Information

High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio.

Publications

High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio.

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