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Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

ABSTRACT: Osteocyte apoptosis is the first reaction to estrogen depletion, thereby stimulating osteoclastic bone resorption resulting in bone loss. We investigated the effects of two different risedronate (RIS) doses (high and low) on osteocyte apoptosis, osteoclast activity and bone loss in ovariectomized rats. Forty rats with ovariectomy (OVX) and sham ovariectomy (SHAM) were divided into 4 groups: 1) SHAM rats treated with saline (SHAM); 2) OVX rats treated with saline (OVX); 3) OVX rats treated with low-dose RIS (OVX-LR, 0.08 ?g/kg/day); 4) OVX rats treated with high-dose RIS (OVX-HR, 0.8 ?g/kg/day). All animals were sacrificed 90 days after surgery for the examinations of osteocyte apoptosis by caspase-3 staining, osteoclast activity by TRAP staining and bone volume by micro-CT scanning in lumbar vertebral cancellous bone. Both low and high dose RIS significantly reduced caspase-3 positive osteocytes, empty lacunae and TRAP positive osteoclasts in OVX rats. Although the difference in caspase-3 positive osteocytes was not significant between the OVX-LR and OVX-HR groups, numerically these cells were significantly more prevalent in OVX-HR (not OVX-LR) group than in SHAM group. TRAP positive osteoclasts were significantly higher in OVX-LR group than in SHAM or OVX-HR group. There was no significant difference in bone volume among the OVX-LR, OVX-HR and SHAM groups, but lower in OVX group alone. However, significant increase in trabecular thickness only occurred in OVX-LR group. We conclude that both low and high dose RIS significantly inhibit osteocyte apoptosis and osteoclast activity in OVX rats, but the low-dose RIS has weaker effect on osteoclast activity. However, low-dose RIS preserves cancellous bone mass and microarchitecture as well as high-dose RIS after estrogen depletion.

SUBMITTER: Ye T

PROVIDER: S-EPMC5646759 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

Ye Tingjun T Cao Peng P Qi Jin J Zhou Qi Q Rao D Sudhaker DS Qiu Shijing S

PloS one 20171018 10

Osteocyte apoptosis is the first reaction to estrogen depletion, thereby stimulating osteoclastic bone resorption resulting in bone loss. We investigated the effects of two different risedronate (RIS) doses (high and low) on osteocyte apoptosis, osteoclast activity and bone loss in ovariectomized rats. Forty rats with ovariectomy (OVX) and sham ovariectomy (SHAM) were divided into 4 groups: 1) SHAM rats treated with saline (SHAM); 2) OVX rats treated with saline (OVX); 3) OVX rats treated with l ...[more]

PMID: 29045447

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Project description:Osteoporosis (OP) is a systemic skeletal disorder, manifesting with a reduction in bone mass and deterioration of the microarchitecture. Mesenchymal stem cells (MSCs) have an innate ability to differentiate into several cell types, including osteoblasts (OB). Ginsenoside Rb1 (GRb1) is an ethanol extract from ginseng and contains a highly concentrated form of ginsenoside. GRb1 shows extensive beneficial health effects such as anti-oxidative and anti-inflammatory functions, modulating the immune system and inhibiting osteoclastogenesis. We hypothesized that GRb1 can promote MSC differentiation into OBs and inhibit bone loss. In the present study, we aimed to address two questions: (1) Will GRb1 have a positive effect on osteogenic differentiation of MSCs? and (2) Will GRb1 halt bone loss in ovariectomized (OVX) rats? We investigated the effects of GRb1 on viability and osteogenic differentiation of rat mesenchymal stem cells (rMSCs). Our results showed that GRb1 at concentrations of 10-8 M and 10-6 M can increase alkaline phosphatase activity, mineralization and the expression of osteogenic related proteins, such as osteopontin and osteoprotegerin, while incubating rMSCs with osteogenic induction medium and GRb1. Adding GRb1 into the medium can prevent rMSCs from Oxidative damage at the concentration of 25?M H2O2. Furthermore, 40 4-month-old rats were assigned to 5 groups(8 rats per group): the basal group, the sham group, the OVX group, the high dose of GRb1 group (6 mg/kg/day) and the low dose of GRb1 group (3 mg/kg/day). Rats recrived treatment 3days after surgery and last for 14 weeks. Examinations included serum analysis, mechanical testing, Masson-Goldner trichrome staining and bone histomorphometry analysis. The results showed that OVX can lead to dyslipidemia and excessive oxidative stress, whereas GRb1 cannot significantly halt dyslipidemia and excessive oxidative stress in OVX rats. In addition, the bone density of the lumbar vertebra and femur were decreased significantly in the OVX rats, and GRb1 could not inhibit bone loss. Bone histomorphometry analysis showed that the number and width of bone trabecula of the tibia were reduced in OVX rats, and GRb1 could not prevent their occurrence. A bone biomechanics assay showed that GRb1 cannot improve the ability of bone structure to resist fracture of the femur in OVX rats. The current study demonstrated that GRb1 has an obvious effect on osteogenic differentiation in rMSCs but no obvious effect on bone loss in OVX rats. These findings indicate GRb1 has a positive effect on rMSCs but does not have an effect on bone loss in OVX rats at the concentration we used.

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.

Project description:Combination therapy of active vitamin D3 with some bisphosphonates (BPs) has been reported to be clinically beneficial. However, combination therapy of eldecalcitol (ELD) with BP has to date not been validated as to whether it is beneficial in the clinical setting. Preclinical studies suggested that simultaneous treatment with ELD and some BPs is more effective than monotherapy. However, the relative potency of various BPs, when used in combination with ELD, is completely unknown. In this study, we examined and compared the effects of risedronate (RIS), alendronate (ALN), and minodronate (MIN) alone or in combination with ELD on bone mass, microarchitecture, strength, and material properties in ovariectomized Sprague-Dawley rats aged 13 weeks. RIS, ALN, MIN, and ELD were administered five times weekly for 16 weeks. Micro-computed tomography analysis, compression test, and Fourier transform infrared (FTIR) imaging analysis were performed 16 weeks after treatment initiation. Trabecular and cortical bone mineral density (BMD) in the fourth lumbar vertebra (L4) significantly increased in the RIS + ELD, ALN + ELD, and MIN + ELD groups compared with the vehicle group. Moreover, the bone microarchitecture of L4 in all the BP + ELD groups also significantly improved. On mechanical testing of L4, the maximum load was significantly increased in the RIS + ELD and ALN + ELD groups. FTIR analysis revealed that the mineral-to-collagen ratio of trabecular bone in L3 of all the BP + ELD groups was significantly increased compared with the vehicle group. By contrast, the carbonate-to-phosphate ratio, a parameter of mineral immaturity, was significantly decreased in the RIS + ELD and ALN + ELD groups. BP + ELD improved the BMD and structural properties of the bone to a similar extent. RIS + ELD and ALN + ELD also improved bone strength. Furthermore, treatment with BP + ELD improved the bone material. These results suggest that the combination therapy of BP and ELD is beneficial and warrants further clinical trials.

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Dataset Information

Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

Publications

Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

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