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Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice.

ABSTRACT: The gap junction protein, connexin43 (Cx43) is involved in mechanotransduction in bone. Recent studies using in vivo models of conditional Cx43 gene (Gja1) deletion in the osteogenic linage have generated inconsistent results, with Gja1 ablation resulting in either attenuated or enhanced response to mechanical load, depending upon the skeletal site examined or the type of load applied. To gain further insights on Cx43 and mechanotransduction, we examined bone formation response at both endocortical and periosteal surfaces in 2-month-old mice with conditional Gja1 ablation driven by the Dermo1 promoter (cKO). Relative to wild type (WT) littermates, it requires a larger amount of compressive force to generate the same periosteal strain in cKO mice. Importantly, cKO mice activate periosteal bone formation at a lower strain level than do WT mice, suggesting an increased sensitivity to mechanical load in Cx43 deficiency. Consistently, trabecular bone mass also increases in mutant mice upon load, while it decreases in WT. On the other hand, bone formation actually decreases on the endocortical surface in WT mice upon application of axial mechanical load, and this response is also accentuated in cKO mice. These changes are associated with increase of Cox-2 in both genotypes and further decrease of Sost mRNA in cKO relative to WT bones. Thus, the response of bone forming cells to mechanical load differs between trabecular and cortical components, and remarkably between endocortical and periosteal envelopes. Cx43 deficiency enhances both the periosteal and endocortical response to mechanical load applied as axial compression in growing mice.

SUBMITTER: Grimston SK

PROVIDER: S-EPMC3438198 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice.

Grimston Susan K SK Watkins Marcus P MP Brodt Michael D MD Silva Matthew J MJ Civitelli Roberto R

PloS one 20120910 9

The gap junction protein, connexin43 (Cx43) is involved in mechanotransduction in bone. Recent studies using in vivo models of conditional Cx43 gene (Gja1) deletion in the osteogenic linage have generated inconsistent results, with Gja1 ablation resulting in either attenuated or enhanced response to mechanical load, depending upon the skeletal site examined or the type of load applied. To gain further insights on Cx43 and mechanotransduction, we examined bone formation response at both endocorti ...[more]

PMID: 22970183

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Project description:Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4?Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1,200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p?<?0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. -1,000??? and a transition from lamellar-woven bone near -2,000???. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1,200 to 300 to 60 did not diminish the bone formation response (p?>?0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p?<?0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to -1,800??? peak strain, at 4?Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month-old C57Bl/6 female mice. Our results provide a basis for reduction of loading duration (daily cycles and study length) without loss of anabolic effect as measured by dynamic histomorphometry. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:682-691, 2018.

Project description:The capacity of bone to optimize its structure in response to mechanical loads has been widely observed. The mechanical load acting on a bone at the macroscopic level influences the bone cells, particularly osteocytes within the lacunae canalicular network (LCN). Osteocytes are responsive to a range of physical signals, including strain, interstitial fluid flow, and pore pressure. However, physiological tissue strain is known to be typically smaller than that required to directly induce bone formation. On the other hand, as per evidence provided by this study from the literature, models based on fluid flow alone cannot simultaneously predict bone formation at both the periosteal and endocortical surfaces. This suggests that another component of the osteocyte's mechanical environment, such as pore pressure, may play an essential role in bone adaptation, either alone or in combination with other stimuli, such as tissue strain and/or interstitial fluid flow. In vitro experiments have also confirmed that osteocytes respond to cyclic pore pressure and, thus, have a mechanism to sense the pressure, possibly because of its viscoelasticity. In this work, dissipation energy density, being irreversible work done per unit volume, has been successfully used as a greater stimulus to incorporate all of the parameters of mechanical environments of the LCN, such as waveforms of both fluid velocity and pore pressure, number of loading cycles. Mineral Apposition Rate (MAR) has also been mathematically derived to be proportional to the square root of the dissipation energy density minus its reference value. A hypothesis is accordingly proposed and successfully tested/validated for both endocortical and periosteal surfaces with respect to an in-vivo study on mouse tibia available in the literature. The constant of proportionality and the reference/threshold value of the dissipation energy density are determined through a nonlinear curve fitting. The mathematical/computational method thus developed is then successfully used to predict MAR at both endocortical and periosteal surfaces induced by a different loading condition. Computational implementation of the mathematical model has been done through a poroelastic finite element analysis of bone, where bone is assumed to be porous and filled with fluid, with a boundary condition that the periosteum is impermeable to the fluid and the endosteal surface maintains a reference zero pressure. This work also provides evidence for these assumptions to be true based on the state-of-the-art literature on related experimental studies. The currently developed model shows that the bone uses these conditions (assumptions) to its advantage, as the greater stimulus, i.e., the dissipation energy due to both fluid flow and pore pressure, are of a similar order at both the surfaces, and hence osteogenesis of the same order at both the surfaces. As a bottom line, the resulting model is the first of its kind as it has been able to correctly predict MAR at both endocortical and periosteal surfaces. This study thus significantly advances the modeling of cortical bone adaptation to exogenous mechanical loading.

Project description:The aim of the current study was to quantify the local effect of mechanical loading on cortical bone formation response at the periosteal surface using previously obtained μCT data from a mouse tibia mechanical loading study. A novel image analysis algorithm was developed to quantify local cortical thickness changes (ΔCt.Th) along the periosteal surface due to different peak loads (0N ≤ F ≤ 12N) applied to right-neurectomised mature female C57BL/6 mice. Furthermore, beam analysis was performed to analyse the local strain distribution including regions of tensile, compressive, and low strain magnitudes. Student's paired t-test showed that ΔCt.Th in the proximal (25%), proximal/middle (37%), and middle (50%) cross-sections (along the z-axis of tibia) is strongly associated with the peak applied loads. These changes are significant in a majority of periosteal positions, in particular those experiencing high compressive or tensile strains. No association between F and ΔCt.Th was found in regions around the neutral axis. For the most distal cross-section (75%), the association of loading magnitude and ΔCt.Th was not as pronounced as the more proximal cross-sections. Also, bone formation responses along the periosteum did not occur in regions of highest compressive and tensile strains predicted by beam theory. This could be due to complex experimental loading conditions which were not explicitly accounted for in the mechanical analysis. Our results show that the bone formation response depends on the load magnitude and the periosteal position. Bone resorption due to the neurectomy of the loaded tibia occurs throughout the entire cross-sectional region for all investigated cortical sections 25, 37, 50, and 75%. For peak applied loads higher than 4 N, compressive and tensile regions show bone formation; however, regions around the neutral axis show constant resorption. The 50% cross-section showed the most regular ΔCt.Th response with increased loading when compared to 25 and 37% cross-sections. Relative thickness gains of approximately 70, 60, and 55% were observed for F = 12 N in the 25, 37, and 50% cross-sections. ΔCt.Th at selected points of the periosteum follow a linear response with increased peak load; no lazy zone was observed at these positions.

Dataset Information

Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice.

Publications

Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice.

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