Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength

Perrien, Daniel S.; Akel, Nisreen; Edwards, Paul; Carver, Adam A.; Bendre, Manali S; Swain, Frances L.; Skinner, Robert A.; Hogue, William R.; Nicks, Kristy M.; Pierson, Tyler Mark; Suva, Larry J.; Gaddy, Dana

doi:10.1210/en.2006-0848

Cited by 99 publications

(104 citation statements)

References 91 publications

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“…(31) This is also consistent with the observation that inhibin-A, which also blocks activin-A, is a stimulator of bone mass and strength. (29) In addition to investigating the effects of activin-A and ActRIIA.muFc on osteoblastogenesis, we also examined their effects on osteoclast formation. We found that activin-A did not significantly alter osteoclast number or activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…(24)(25)(26)(27) In vivo, direct administration of activin-A increases bone mineral density (BMD), (28) whereas overexpression of inhibin-A, which blocks activin-A and other TGF-b family members, increases bone mass. (29,30) We have demonstrated recently that activin-A signaling can be blocked in vivo with a soluble ActRIIA.muFc fusion protein, leading to increased bone mass and strength. (31) Levels of activin-A have been shown to be increased in the sera of patients with breast and prostate cancer and to be increased further in the presence of metastases.…”

Section: J Jbmrmentioning

confidence: 99%

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Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Chantry

Heath

Mulivor

et al. 2010

Journal of Bone and Mineral Research

135

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Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis ( p < .01), promotes bone formation ( p < .01) and increases bone mass in vivo ( p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption ( p < .05) and suppression of bone formation ( p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis ( p < .01), prevents myeloma-induced suppression of bone formation ( p < .05), blocks the development of osteolytic bone lesions ( p < .05), and increases survival ( p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction ( p < .001) and inhibits bone metastases ( p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. ß

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Section: Discussionmentioning

confidence: 99%

Section: J Jbmrmentioning

confidence: 99%

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Chantry

Heath

Mulivor

et al. 2010

Journal of Bone and Mineral Research

135

View full text Add to dashboard Cite

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“…32 Thawed specimens were soaked in saline for 1 hour before testing to ensure hydration and then tested at room temperature using a servohydraulic-testing machine MTS 858 Bionex test systems load frame (MTS, Eden Prairie, MN) with computer control, data logging, and calculations of load to failure using TestWorks version 4.0 (MTS). Bones were placed with their anterior side down on two horizontal supports spaced 7 mm apart; the central loading point contacted the posterior surface of the diaphysis at the midpoint of the bone length.…”

Section: Whole Femur Mechanical Testingmentioning

confidence: 99%

“…Loaddisplacement data were recorded at 100 Hz (TestWorks 4.0, MTS), and test curves were analyzed to determine measures of whole-bone strength, primarily peak load and stiffness as we have described. 32 Load to failure was recorded as the load after a 2% drop from peak load.…”

Section: Whole Femur Mechanical Testingmentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

Self Cite

110

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The platelet glycoprotein Ib-IX receptor binds surfacebound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. (Am J

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“…24 Moreover, mFEA of excised bones is non-destructive allowing for subsequent histological analysis. Although a number of studies involving rodents have used mFEA to determine the effect of drug treatment on bone strength, [25][26][27][28][29][30] there is little evidence in the literature establishing that mFEA can accurately predict the mechanical properties of rodent bone, and especially murine bones. Of the few studies comparing FEA predictions to experimental measurements of strength in rodent tissues, long bones were tested with limited examination of material definitions.…”

Section: Introductionmentioning

confidence: 99%

Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis

Nyman¹,

Uppuganti²,

Makowski³

et al. 2015

BoneKEy Reports

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As in clinical studies, finite element analysis (FEA) developed from computed tomography (CT) images of bones are useful in pre-clinical rodent studies assessing treatment effects on vertebral body (VB) strength. Since strength predictions from microCT-derived FEAs (mFEA) have not been validated against experimental measurements of mouse VB strength, a parametric analysis exploring material and failure definitions was performed to determine whether elastic mFEAs with linear failure criteria could reasonably assess VB strength in two studies, treatment and genetic, with differences in bone volume fraction between the control and the experimental groups. VBs were scanned with a 12-mm voxel size, and voxels were directly converted to 8-node, hexahedral elements. The coefficient of determination or R 2 between predicted VB strength and experimental VB strength, as determined from compression tests, was 62.3% for the treatment study and 85.3% for the genetic study when using a homogenous tissue modulus (E t ) of 18 GPa for all elements, a failure volume of 2%, and an equivalent failure strain of 0.007. The difference between prediction and measurement (that is, error) increased when lowering the failure volume to 0.1% or increasing it to 4%. Using inhomogeneous tissue density-specific moduli improved the R 2 between predicted and experimental strength when compared with uniform E t ¼ 18 GPa. Also, the optimum failure volume is higher for the inhomogeneous than for the homogeneous material definition. Regardless of model assumptions, mFEA can assess differences in murine VB strength between experimental groups when the expected difference in strength is at least 20%.

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Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength

Cited by 99 publications

References 91 publications

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis

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