Whole Bone Mechanics and Bone Quality

Cole, Jacqueline H.; Meulen, Marjolein C. H. van der

doi:10.1007/s11999-011-1784-3

Cited by 136 publications

(112 citation statements)

References 132 publications

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“…The mechanical strength of the bone is the ultimate predictor of fracture risks (19). To investigate whether the increase in bone formation following the PGK-PDGFB treatment can be translated into an increase in bone strength, we subjected the Lenti-PGK-PDGFBtreated and the Lenti-GFP-treated control femur to three-point bending mechanical testing.…”

Section: Resultsmentioning

confidence: 99%

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Chen

Baylink

Brier-Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1 + cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1 + cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.PDGFB | hematopoietic stem cells | bone formation | gene therapy

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Section: Resultsmentioning

confidence: 99%

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Chen

Baylink

Brier-Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Though bone fragility, or the susceptibility to fracture, is often considered a key indicator of the health or quality of bone, the term "bone quality" actually refers to many characteristics that contribute to its load--bearing ability. These include bone mass, density, geometry, architecture, rate of turnover, tissue composition, mineralization, and mechanical properties 224,226,227 .…”

Section: Bone Qualitymentioning

confidence: 99%

“…In cortical bone, bone mass is measured as bone mineral content, and is reflected in geometric properties such as cross--sectional area, moment of inertia, and section modulus. In trabecular bone, the structure is more complex, and bulk cancellous bone mass is quantified as the bone volume fraction within a total tissue volume (BV/TV) 226 .…”

Section: Bone Mass and Densitymentioning

confidence: 99%

“…Tissue distribution is dependent upon geometric parameters such as cross--sectional area, moment of inertia, and section modulus, with the relevance of different geometric parameters dependent upon the particular mode of applied load. In bending and torsion, resistance to loading can be increased if the tissue is located farther away from the plane of bending or the axis of rotation, such that changes in bone mass at critical locations can have a disproportionate effect on the structural performance of bone 226 . For instance, the outer surface of a solid cylinder better resists bending forces than its inner core, such that the loss of bone mass in the center only slightly reduces the bone's strength in bending (Figure 1-21).…”

Section: Geometry and Architecturementioning

confidence: 99%

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Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Liu¹,

Young²,

Grynpas³

2013

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Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti--resorptive agent (alendronate) through a linker. This allows the bone--targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose--dependently stimulated bone formation and restored ovariectomy--induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug's anabolic effect.iii

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“…Because bone's structural mechanical properties are more closely associated with fracture risk than BMD or bone architecture [16,17], these efforts were expanded to determine genetic locations that modulate bone's mechanical properties including failure load, stiffness, or yield strength. Because of the greater complexity determining bone's mechanical properties rather than BMD or morphology, relatively little is known about mechanical genotype/phenotype relations.…”

Section: Introductionmentioning

confidence: 99%

Quantitative trait loci that modulate trabecular bone's risk of failure during unloading and reloading

Özçivici

Zhang

Donahue

et al. 2014

Bone

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Genetic makeup of an individual is a strong determinant of the morphologic and mechanical properties of bone. Here, in an effort to identify quantitative trait loci (QTLs) for changes in the simulated mechanical parameters of trabecular bone during altered mechanical demand, we subjected 352 second generation female adult (16 weeks old) BALBxC3H mice to 3 weeks of hindlimb unloading followed by 3 weeks of reambulation. Longitudinal in vivo microcomputed tomography (μCT) scans tracked trabecular changes in the distal femur. Tomographies were directly translated into finite element (FE) models and subjected to a uniaxial compression test. Apparent trabecular stiffness and components of the Von Mises (VM) stress distributions were computed for the distal metaphysis and associated with QTLs. At baseline, five QTLs explained 20% of the variation in trabecular peak stresses across the mouse population. During unloading, three QTLs accounted for 14% of the variability in peak stresses. During reambulation, one QTL accounted for 5% of the variability in peak stresses. QTLs were also identified for mechanically induced changes in stiffness, median stress values and skewness of stress distributions. There was little overlap between QTLs identified for baseline and QTLs for longitudinal changes in mechanical properties, suggesting that distinct genes may be responsible for the mechanical response of trabecular bone. Unloading related QTLs were also different from reambulation related QTLs. Further, QTLs identified here for mechanical properties differed from previously identified QTLs for trabecular morphology, perhaps revealing novel gene targets for reducing fracture risk in individuals exposed to unloading and for maximizing the recovery of trabecular bone's mechanical properties during reambulation.© 2014 Elsevier Inc. All rights reserved. IntroductionA principal function of bone is to withstand mechanical loads acting upon it. Through its capacity for dynamic remodeling, bone tissue processes external physical signals as informative cues to adapt its mass, structure and mechanical properties [1,2]. Mechanical loads are required for bone maintenance and growth while unloading causes erosion of bone morphology and strength [3][4][5]. Inherently, the relation between loading and specific bone variables is regulated at the genetic level. Interestingly, bone does not necessarily perceive and process similar mechanical cues in the same manner across individuals with different genotypes, giving rise to substantially different molecular and morphologic outcomes [6][7][8]. The identity of the genetic locations regulating bone's response to (un)loading, while largely unknown, would provide targets towards protecting individuals from bone loss during deprivation of mechanical loads and maximizing bone gain during the application of loads.In the absence of differences in the mechanical loading environment, many studies have investigated quantitative trait loci (QTLs) and the associated genetic polymorphisms that explain variation...

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Whole Bone Mechanics and Bone Quality

Cited by 136 publications

References 132 publications

PDGFB-based stem cell gene therapy increases bone strength in the mouse

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Quantitative trait loci that modulate trabecular bone's risk of failure during unloading and reloading

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