Dataset Information

In Vivo Bone Effects of a Novel Bisphosphonate-EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model.

ABSTRACT: Pathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12?weeks, seven groups of rats were treated for 8?weeks via tail-vein injection. The groups were: C3 conjugate at low and high doses, vehicle-treated ovariectomy (OVX) and sham, C1 (a similar conjugate, but with active ALN at high dose), inactive ALN alone, and a mixture of unconjugated ALN and EP4a to evaluate the conjugation effects. Bone turnover was determined by dynamic and static histomorphometry; ?CT was employed to determine bone microarchitecture; and bone mechanical properties were evaluated via biomechanical testing. Treatment with C3 significantly increased trabecular bone volume and vertebral BMD versus OVX controls. There was also significant improvement in the vertebral load-bearing abilities and stimulation of bone formation in femurs after C3 treatment. This preclinical research revealed that C3 resulted in significant anabolic effects on trabecular bone, and EP4a and ALN conjugation components are vital to conjugate anabolic efficacy. A combined therapy using an EP4 selective agonist anabolic agent linked to an inactive ALN is presented here that produces significant anabolic effects, allows bone remodeling, and has the potential for treating postmenopausal osteoporosis or other diseases where bone strengthening would be beneficial. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Sheikh Z

PROVIDER: S-EPMC6894726 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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In Vivo Bone Effects of a Novel Bisphosphonate-EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model.

Sheikh Zeeshan Z Chen Gang G Al-Jaf Faik F Thévenin Marion M Banks Kate K Glogauer Michael M Young Robert N RN Grynpas Marc D MD

JBMR plus 20191109 12

Pathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12 weeks, seven groups of rats were treated for 8 weeks via tail-vein ...[more]

PMID: 31844825

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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:Mesenchymal stem cells (MSCs) have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1) Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2) Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX) rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX) and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91). Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn't show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study demonstrated that systemic administration of allogenic MSCs had no obvious effect on osteoporotic bone loss in OVX rats when using the cells from the same donor; and repeated injection of allogeneic MSCs from different donors might promote bone loss in OVX rats. These findings indicate that despite allogenic MSCs systemic infusion is safe, their administration alone may not be an effective mean for preventing osteoporotic bone loss.

Dataset Information

In Vivo Bone Effects of a Novel Bisphosphonate-EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model.

Publications

In Vivo Bone Effects of a Novel Bisphosphonate-EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model.

Similar Datasets

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