Prevention of glucocorticoid induced bone changes with beta-ecdysone

Dai, Weiwei; Jiang, Li; Lay, Yu-An E.; Chen, Haiyan; Jin, G Q; Zhang, Hongliang; Kot, Alexander; Ritchie, Robert O.; Lane, Nancy E.; Yao, Wei

doi:10.1016/j.bone.2015.01.001

Cited by 26 publications

(21 citation statements)

References 70 publications

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“…A standard curve was generated from each kit, and the absolute concentrations were extrapolated from the standard curves. The coefficients of variations for inter-assay and intra-assay measurements were < 10% for all assays and are similar to the manufacturers’ references [28,29]. …”

Section: Methodssupporting

confidence: 81%

“…The tests were performed in 37 °C HBSS and sample loads and displacements were continuously recorded throughout each test. Values for the maximum load were determined as previously described [29]. To analyze the biomechanical properties of the femurs, the samples were subjected to three-point bending tests using a MTS 831 electro-servo-hydraulic testing system (MTS Systems Corp., Eden Prairie, MN, USA) such that the posterior surface was in tension and the anterior surface was in compression [29].…”

Section: Methodsmentioning

confidence: 99%

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A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis

et al. 2016

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Prolonged glucocorticoid (GC) administration causes secondary osteoporosis (GIOP) and non-traumatic osteonecrosis. LLP2A-Ale is a novel bone seeking compound that recruits mesenchymal stem cells to the bone surface, stimulates bone formation, and increases bone mass. The purpose of this study was to determine if treatment with LLP2A-Ale alone or in combination with parathyroid hormone (PTH) could prevent or treat GIOP in a mouse model. Four month old male Swiss-Webster mice were randomized to a prevention study with placebo, GC (day 1 – 28), and GC + LLP2A-Ale (IV, day 1) or a treatment study with placebo, GC (day 1 – 56), GC + LLP2A-Ale (IV, day 28), GC + PTH, and GC + LLP2A-Ale + PTH (day 28 – 56). Mice were sacrificed on day 28 (prevention study) or on day 56 (treatment study). The study endpoints included bone mass, bone strength, serum markers of bone turnover (P1NP and CTX-I) and angiogenesis (VEGF-A), surface-based bone turnover, and blood vessel density. LLP2A-Ale prevented GC-induced bone loss and increased mechanical strength in the vertebral body (day 28 and 56) and femur (day 56). LLP2A-Ale, PTH, and LLP2A-Ale + PTH treatment significantly increased the mineralizing surface, bone formation rate, mineral apposition rate, double labeled surface and serum P1NP level on day 56. LLP2A-Ale and PTH treatment increased femoral blood vessel density and LLP2A-Ale increased serum VEGF-A on day 28. Therefore, LLP2A-Ale monotherapy could be a potential option to both prevent and treat GC-induced osteoporosis and bone fragility.

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Section: Methodssupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis

et al. 2016

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“…We have demonstrated that GC treatment of mice resulted in an early elevation in the expression of genes involved with osteoclast activities within the first 7 days of GC exposure [3], which was followed by a delayed but prolonged suppression of osteoblastogenesis [3, 68] with reduced bone formation measured by serum osteocalcin and surface-based histomorphometry [34]. Indeed, GC doses of 4 mg/kg significantly reduced the percentages of osteoblasts that underwent autophagy, suppressed bone formation at all bone surfaces, and reduced bone strength at both the trabecular and cortical bone.…”

Section: Discussionmentioning

confidence: 99%

“…For the right mid-femur, the scanning was performed at the middle femur and continued proximally 0.5 mm. All the slides were used to evaluate total volume (TV), cortical bone volume (BV), and cortical thickness (Ct.Th) [32–34]. …”

Section: Methodsmentioning

confidence: 99%

Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength

et al. 2015

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Summary This study was to determine if antibody against sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced osteoporosis in mice. We found that Scl-Ab prevented GC-induced reduction in bone mass and bone strength and that the anabolic effects of Scl-Ab might be partially achieved through the preservation of osteoblast activity through autophagy. Introduction Glucocorticoids (GCs) inhibit bone formation by altering osteoblast and osteocyte cell activity and lifespan. A monoclonal antibody against sclerostin, Scl-Ab, increased bone mass in both preclinical animal and clinical studies in subjects with low bone mass. The objectives of this study were to determine if treatment with the Scl-Ab could prevent loss of bone mass and strength in a mouse model of GC excess and to elucidate if Scl-Ab modulated bone cell activity through autophagy. Methods We generated reporter mice that globally expressed dsRed fused to LC3, a protein marker for autophagosomes, and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8, and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength. Results GC treatment at 2.8 and 4 mg/kg/day of methylprednisolone significantly lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the mid-shaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60–125 %, apparent bone strength of the lumbar vertebrae by 30–70 %, FS-BV by 10–18 %, and FS-apparent strength by 13–15 %, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/ day reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the placebo group (PL, GC 0 mg), and GC + Scl-Ab treatment. Conclusions Treatment with Scl-Ab prevented GC-induced reduction in both trabecular and cortical bone mass and strength and appeared to maintain osteoblast activity through autophagy.

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“…The mice were randomized into groups with eight to 11 per group: Group 1, male controls treated with phosphate-buffered saline (vehicle; Male); Group 2, males treated with bEcd (Male + bEcd 0.5 mg/kg, 59/week); Group 3, female controls treated with phosphate-buffered saline (vehicle; Female); Group 4, females treated with bEcd (Female + bEcd 0.5 mg/kg, 59/week). The b-Ecd dose was chosen from a pilot dose-response study we performed on male mice with doses of 0.25 to 1 mg/kg [12].…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

β-Ecdysone Augments Peak Bone Mass in Mice of Both Sexes

Dai

Zhang

Zhong

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background One of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. b-Ecdysone (bEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass. Questions/purposes The purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after bEcd administration.Methods Two-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or bEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of bEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Shamoperated and the ORX/OVX mice were then treated for 3 weeks with bEcd. Primary endpoints for the study were trabecular bone structure and bone strength. Results In male mice, the trabecular bone volume was 0.18 ± 0.02 in the placebo-treated (PL) and 0.23 ± 0.02 in the bEcd-treated group (p \ 0.05 versus PL); and 0.09 ± 0.01 in the ORX group (p \ 0.05 versus PL) and 0.12 ± 0.01 in the ORX + bEcd group. Vertebral bone strength (maximum load) was 43 ± 2 in PL and 51 ± 1 in the bEcd-treated group (p \ 0.05 versus PL); and 30 ± 4 in the ORX group (p \ 0.05 versus PL) and 37 ± 3 in the ORX + bEcd group. In female mice, trabecular bone volume was 0.23 ± 0.02 in PL and 0.26 ± 0.02 in the bEcd-treated group (p \ 0.05 versus PL); and 0.15 ± 0.01 in the OVX group (p \ 0.05 versus PL) and 0.14 ± 0.01 in the OVX + bEcd group. Maximum load of the vertebrae was 45 ± 2 in PL and 48 ± 4 in the bEcd-treated group; and 39 ± 4 in the OVX group (p \ 0.05 versus PL) and 44 ± 4 in the OVX + bEcd group.

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Prevention of glucocorticoid induced bone changes with beta-ecdysone

Cited by 26 publications

References 70 publications

A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis

A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis

Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength

β-Ecdysone Augments Peak Bone Mass in Mice of Both Sexes

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