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[Prolonged continuous infusion of teriparatide promotes bone metabolism in normal but not in castrated mice].

ABSTRACT: OBJECTIVE:To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts. METHODS:Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) via a micropump (SHAM-VEH, SHAM-TPTD, OVX-VEH, and OVX-TPTD groups; n=6). Two weeks later, the tibial and femoral bones were harvested for micro-CT scanning to measure the parameters of the tibia and the femoral cortical bone. Histopathological examinations of the tibial tissue were conducted using HE staining and TRAP staining and the number of osteoclasts and the growth plate thickness were determined. The serum Ca2 + levels of the mice were measured. The primary osteoblasts from the cranial bone were treated with estradiol (E2) and TPTD for 48 h, and the expressions of ?-catenin and RANKL protein in the cells were analyzed. RESULTS:The trabecular bone mass of OVX mice was significantly lower than that of sham-operated mice (P < 0.05). Continuous TPTD pumping significantly reduced tibial cancellous bone mass and femoral cortical bone area in the sham-operated mice, while in the castrated mice, TPTD pumping increased the cancellous bone mass without changing the cortical bone area. TRAP staining showed that cancellous osteoblasts in the tibia increased significantly in the castrated mice as compared with the sham-operated mice, and TPTD pumping significantly increased the number of cancellous osteoblasts in the sham-operated mice (P < 0.05). In the primary cultured osteoblasts, treatment with both E2 and TPTD obviously lowered the expression of ?-catenin and increased the expression of RANKL as compared with TPTD treatment alone. CONCLUSIONS:Continuous pumping of TPTD promotes bone resorption in normal mice but does not produce obvious bone resorption effect in the ovariectomized mice, suggesting that castrated mice are not suitable models for studying the effect of TPTD and the related peptides on the osteoclasts.

SUBMITTER: Li M

PROVIDER: S-EPMC6881736 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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[Prolonged continuous infusion of teriparatide promotes bone metabolism in normal but not in castrated mice].

Li Minghan M He Youhua Y Tong Guojun G Yang Dehong D

Nan fang yi ke da xue xue bao = Journal of Southern Medical University 20190901 9

<h4>Objective</h4>To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts.<h4>Methods</h4>Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) <i>via</i> a micropu ...[more]

PMID: 31640962

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Project description:Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide.

Project description:ObjectiveKnee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms.MethodsIn vivo study, eight-week-old male mice including wild-type (WT) (n = 54) and OPG-/- (n = 54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n = 18), the DMM group (WT-DMM; n = 18), and the PTH (1-34)-treated group (WT-DMM + PTH (1-34); n = 18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro.ResultsCompared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6).ConclusionBoth wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA.The translational potential of this articleSystemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.

Project description:20-Hydroxyecdysone (20E) is the most abundant phytoecdysteroid produced by several plant families and has been attributed with numerous pharmacological properties in animals including anabolic and immune modulating effects. However, the in vivo bioactivity of phytoecdysteroids in mammals remains ambiguous, and moreover, the mechanism of action in mammals has yet to be determined. In this study, the physiological and gene expression effects of 20E were analyzed in C57BL/6 mice given a continuous infusion of saline or 20E (5 mg/kg/day) for five or fifteen days using subcutaneously implanted Alzet® osmotic pumps. The weights of the total body, muscle groups and organs were recorded and carcass composition was determined to evaluate changes in nutrient partitioning. There was a significant increase (p = 0.01) in the weight of triceps brachii in mice treated with 20E for five days (115 +/- 8 mg) compared to mice treated with saline for five days (88 +/- 3 mg), however, there were no differences in the other measured parameters. To determine potential mechanisms of action of 20E in skeletal muscle, Illumina’s Mouse Whole Genome-6 v2.0 Expression BeadChips were used to evaluate changes in gene expression after 20E infusion. False Discovery Rate correction of microarray data did not reveal any beadtypes that were differentially expressed. Therefore, Ingenuity Pathways Analysis (IPA) was used to identify genes with the most evidence for differential expression in the context of biological functions and pathways. IPA provided evidence for 20E involvement in processes including cellular growth and proliferation and cell-to-cell signaling and interaction. Overall, the data suggests that 20E does not have potent anabolic properties. IPA identified potential lead biological processes and pathways of 20E. Total RNA was extracted from the triceps brachii of C57BL/6 mice given a continuous infusion of saline or 20E (5 mg/kg/day) for 5 or 15 days using subcutaneously implanted Alzet® osmotic pumps to evaluate gene expression effects of 20E on mouse muscle.

Dataset Information

[Prolonged continuous infusion of teriparatide promotes bone metabolism in normal but not in castrated mice].

Publications

[Prolonged continuous infusion of teriparatide promotes bone metabolism in normal but not in castrated mice].

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