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Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength.

ABSTRACT: Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption.To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks.Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for µCT and mechanical testing. An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. µCT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone.In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength.

SUBMITTER: Henriksen K

PROVIDER: S-EPMC3210177 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength.

Henriksen Kim K Flores Carmen C Thomsen Jesper S JS Brüel Anne-Marie AM Thudium Christian S CS Neutzsky-Wulff Anita V AV Langenbach Geerling E J GE Sims Natalie N Askmyr Maria M Martin Thomas J TJ Everts Vincent V Karsdal Morten A MA Richter Johan J

PloS one 20111107 11

Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption.To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have def ...[more]

PMID: 22087326

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Project description:Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. INTRODUCTION:Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). METHODS:Sixty-five 9-18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n?=?17) or abaloparatide (0.2, 1, or 5 ?g/kg/day; n?=?16/dose level), while Sham controls received s.c. vehicle (n?=?15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. RESULTS:At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. CONCLUSIONS:Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters.

Dataset Information

Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength.

Publications

Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength.

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