Intracortical Bone Remodeling Variation Shows Strong Genetic Effects

Authors

L. M. Havill, M. R. Allen, J. A. K. Harris, S. M. Levine, H. B. Coan, M. C. Mahaney, D. P. Nicolella

Abstract

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7–33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h 2]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h 2 = 0.79, p = 0.002), %On.B (h 2 = 0.82, p = 0.003), and W.Th (h 2 = 0.61, p = 0.013), indicating that 61–82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48–75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Link to Article

http://dx.doi.org/10.1007/s00223-013-9775-x

Production and repair of implant-induced microdamage in the cortical bone of goats after long-term estrogen deficiency

Authors

Z. Yu, G. Wang, T. Tang, L. Fu, X. Yu, L. Cao, Z. Zhu, K. Dai, S. Qiu

Abstract

Summary: By using an ovariectomized goat model, we found that estrogen depletion decreases bone quality and makes it susceptible to screw-induced mechanical microdamage. Both diffuse microdamage and linear cracks accumulated up to 3 weeks after screw implantation, and the microdamage was repaired gradually after 4–8 months. Introduction: The aim of this study was to observe the effect of long-term estrogen deficiency on the creation and repair of microdamage in cortical bone adjacent to bone screw. Methods: Cortical bone screws were placed in the tibial diaphyses 28 months after ovariectomy (OVX) or sham operation (Sham-Op) in female goats. The goats were euthanized at 0 day, 21 days, 4 months, and 8 months after screw implantation. Microdamage morphology and repair were examined in peri-screw bone using histomorphometric method, and the nanomechanical properties of peri-screw bone were examined with nanoindentation testing. Results: Tibiae from ovariectomized goats in which screws had been placed had significantly higher levels of diffuse microdamage and significantly more linear cracks than those from sham goats, and the diffuse microdamage was more obvious than linear cracks in the region adjacent to the implant. Both diffuse microdamage and linear cracks accumulated up to day 21 and then gradually repaired at 4 and 8 months after surgery. The trend for bone remodeling in each group was consistent with changes in the level of microdamage. Nanoindentation testing showed that both elastic modulus and hardness in peri-screw bone were significantly decreased in OVX group compared to Sham-Op group. The hardness and elastic modulus also showed a downward trend up to 4 months after screw implantation and then exhibited some recovery after 8 months. Conclusions: Estrogen depletion decreases bone quality and makes it vulnerable to screw-induced mechanical damage, which may compromise the initial stability of an orthopedic implant.

Link to Article

http://dx.doi.org/10.1007/s00198-013-2496-1

Effect of maxillomandibular fixation on condylar growth in juvenile Macaca mulatta: a cephalometric and histologic study

Authors

Goran Isacsson, David S. Carlson, James A. McNamara, Jr. and Annika M. Isberg

Abstract

The effect of maxillomandibular fixation on the growth of the mandibular condyle was studied in eight control and eight experimental male juvenile monkeys. All animals had metallic implants placed throughout the craniofacial complex in order to facilitate cephalometric analysis of growth-related changes in the maxillomandibular complex during jaw immobilization. Every 3, 6, 12, and 24 wk after insertion of the appliance two experimental animals were killed for histologic analysis. Cephalometric analysis indicated no major deviation from normal maxillary or mandibular growth in the experimental animals. The condylar growth in the experimental animals was comparable with that of the controls. Histologic analysis indicated that the articular connective tissue in experimental joints remained the same thickness as in the controls. On the postero-superior aspect of the condyle, the thickness of the prechondroblastic-chondroblastic cell layer was reduced by 70-80% in the experimental animals. On the posterior aspect this cell layer was not visible after 12 wk of fixation, but was replaced by a periosteum-like, cell-rich tissue which appeared to be active in appositional formation of cancellous bone. These results indicate that long-term maxillomandibular fixation does not cause major alterations in the growth of condyle or the entire mandible despite a profound decrease of the prechondroblastic-chondroblastic cell layer in the postero-superior and posterior regions of the condyle. The growth is probably due to a compensatory appositional bone formation along the surface of the condyle. It is also concluded that jaw mobility is not a prerequisite for normal maxillary or mandibular growth.

Link to Article

http://prod.umdentistry.com/sites/default/files/departments/opd/090.pdf

A Clinically Relevant Mouse Model of Canine Osteosarcoma with Spontaneous Metastasis

Authors

Beth K. Chaffee and Matthew J. Allen

Abstract

Background/Aim: Many patients with osteosarcoma (OS) will succumb to distant metastasis, often involving the lungs. Effective therapies for treating lung metastases depend on the availability of a clinically relevant pre-clinical model. Materials and Methods: Mice were surgically implanted with OS tumor fragments. The time course of primary tumor growth and subsequent spread to the lung were determined. Results: Following development of a lytic and proliferative primary bone lesion, tumor metastasized to the lung in the majority of mice. There was no evidence of tumor at three weeks, but 10 out of 11 mice ultimately developed secondary OS in the lung within 12 weeks. Conclusion: Implantation of OS tumor fragments leads to the development of primary bone tumors and secondary lung metastases, recapitulating the clinical behavior of OS. This model offers an advantage over cell suspension injection models by precluding initial seeding of the lung with tumor cells.

Link to Article

http://iv.iiarjournals.org/content/27/5/599.short

18F-fluoride Positron Emission Tomography Measurements of Regional Bone Formation in Hemodialysis Patients with Suspected Adynamic Bone Disease

Authors

Michelle L. Frost, Juliet E. Compston, David Goldsmith, Amelia E. Moore, Glen M. Blake, Musib Siddique, Linda Skingle, Ignac Fogelman

Abstract

18F-fluoride positron emission tomography (18F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an 18F-PET scan, and bone plasma clearance, K i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K ibetween the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K i corrected for BMAD (K i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of 18F-PET as a diagnostic tool for identifying CKD patients with ABD.

Link to Article

http://dx.doi.org/10.1007/s00223-013-9778-7

R-spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis

Authors

Haitao Wang, Tracy A. Brennan, Elizabeth Russell, Jung-Hoon Kim, Kevin P. Egan, Qijun Chen, Craig Israelite, David C. Schultz, Frederick B. Johnson, Robert J. Pignolo

Abstract

Bone tissue adapts to its functional environment by optimizing its morphology for mechanical demand. Among the mechanosensitive cells that recognize and respond to forces in the skeleton are osteocytes, osteoblasts, and mesenchymal progenitor cells (MPCs). Therefore, the ability to use mechanical signals to improve bone health through exercise and devices that deliver mechanical signals is an attractive approach to age-related bone loss; however, the extracellular or circulating mediators of such signals are largely unknown. Using SDS-PAGE separation of proteins secreted by MPCs in response to low-magnitude mechanical signals and in-gel trypsin digestion followed by HPLC and mass spectroscopy, we identified secreted proteins up-regulated by vibratory stimulation. We exploited a cell senescence-associated secretory phenotype screen and reasoned that a subset of vibration-induced proteins with diminished secretion by senescent MPCs will have the capacity to promote bone formation in vivo. We identified one such vibration-induced bone-enhancing (vibe) gene as R-spondin 1, a Wnt pathway modulator, and demonstrated that it has the capacity to promote bone formation in three mouse models of age-related bone loss. By virtue of their secretory status, some vibe proteins may be candidates for pre-clinical development as anabolic agents for the treatment of osteoporosis.

Link to Article

http://dx.doi.org/10.1007/s00109-013-1068-3