Murine Axial Compression Tibial Loading Model to Study Bone Mechanobiology: Implementing the Model and Reporting Results

Main, Russell P.; Shefelbine, Sandra J.; Meakin, Lee B; Silva, Matthew J.; Meulen, Marjolein C. H. van der; Willie, Bettina M.

doi:10.1002/jor.24466

Cited by 46 publications

(38 citation statements)

References 180 publications

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“…The tibial loading model allows examination of the effects of loading on cortical and cancellous tissues simultaneously within the same bone. ( 26 ) Similar to several other tibial loading studies, ( 29,31 ) we find that a greater load magnitude is required to induce an adaptive bone response in the proximal cancellous bone compared with the diaphyseal cortical bone of the tibia. However, the underlying reason for that was not explored previously, particularly from a perspective of tissue strain.…”

Section: Discussionsupporting

confidence: 87%

“…At 16 weeks of age, mice received unilateral in vivo dynamic compressive loading of the tibia (n = 174). Following Protocol III presented in Main and colleagues, ( 26 ) peak dynamic compressive loads of −3.5 N (low), −5.2 N (medium), and − 7.0 N (high) were applied to the left hindlimb with a single load session consisting of 216 total load events (Supplementary Information Fig. S1 A , B ).…”

Section: Methodsmentioning

confidence: 99%

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Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

et al. 2021

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Strain magnitude has a controlling influence on bone adaptive response. However, questions remain as to how and if cancellous and cortical bone tissues respond differently to varied strain magnitudes, particularly at a molecular level. The goal of this study was to characterize the time‐dependent gene expression, bone formation, and structural response of the cancellous and cortical bone of female C57Bl/6 mice to mechanical loading by applying varying load levels (low: −3.5 N; medium: −5.2 N; high: −7 N) to the skeleton using a mouse tibia loading model. The loading experiment showed that cortical bone mass at the tibial midshaft was significantly enhanced following all load levels examined and bone formation activities were particularly elevated at the medium and high loads applied. In contrast, for the proximal metaphyseal cancellous bone, only the high load led to significant increases in bone mass and bone formation indices. Similarly, expression of genes associated with inhibition of bone formation (e.g., Sost) was altered in the diaphyseal cortical bone at all load levels, but in the metaphyseal cortico‐cancellous bone only by the high load. Finite element analysis determined that the peak tensile or compressive strains that were osteogenic for the proximal cancellous bone under the high load were significantly greater than those that were osteogenic for the midshaft cortical tissues under the low load. These results suggest that the magnitude of the strain stimulus regulating structural, cellular, and molecular responses of bone to loading may be greater for the cancellous tissues than for the cortical tissues. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

et al. 2021

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“…In Vivo Mechanoresponse Experiment and 3D Dynamic In Vivo Morphometry. Two weeks of controlled loading was applied on the left tibia of three skeletally mature (26-wk-old) female C57BL/J6 mice (The Jackson Laboratory) to provoke a bone (re)modeling response (43). The loading protocol (74) and time-lapse imaging method (75) have been previously reported in detail and are only briefly described here.…”

Section: Methodsmentioning

confidence: 99%

The mechanoresponse of bone is closely related to the osteocyte lacunocanalicular network architecture

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et al. 2020

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

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Organisms rely on mechanosensing mechanisms to adapt to changes in their mechanical environment. Fluid-filled network structures not only ensure efficient transport but can also be employed for mechanosensation. The lacunocanalicular network (LCN) is a fluid-filled network structure, which pervades our bones and accommodates a cell network of osteocytes. For the mechanism of mechanosensation, it was hypothesized that load-induced fluid flow results in forces that can be sensed by the cells. We use a controlled in vivo loading experiment on murine tibiae to test this hypothesis, whereby the mechanoresponse was quantified experimentally by in vivo micro-computed tomography (µCT) in terms of formed and resorbed bone volume. By imaging the LCN using confocal microscopy in bone volumes covering the entire cross-section of mouse tibiae and by calculating the fluid flow in the three-dimensional (3D) network, we could perform a direct comparison between predictions based on fluid flow velocity and the experimentally measured mechanoresponse. While local strain distributions estimated by finite-element analysis incorrectly predicts preferred bone formation on the periosteal surface, we demonstrate that additional consideration of the LCN architecture not only corrects this erroneous bias in the prediction but also explains observed differences in the mechanosensitivity between the three investigated mice. We also identified the presence of vascular channels as an important mechanism to locally reduce fluid flow. Flow velocities increased for a convergent network structure where all of the flow is channeled into fewer canaliculi. We conclude that, besides mechanical loading, LCN architecture should be considered as a key determinant of bone adaptation.

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“…Modeling describes the (almost) independent activity of osteoblasts without or with only minimal osteoclast resorptive activity, just adding more mineralized tissue in response to e.g., physical forces through strain and fluid flow. The molecular cascade that follows high-impact strain to bone obviously resembles endochondral bone formation [112].…”

Section: Principles Of Bone Formation Maintenance and Regenerationmentioning

confidence: 99%

Interactions between Muscle and Bone—Where Physics Meets Biology

et al. 2020

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Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.

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Murine Axial Compression Tibial Loading Model to Study Bone Mechanobiology: Implementing the Model and Reporting Results

Cited by 46 publications

References 180 publications

Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

The mechanoresponse of bone is closely related to the osteocyte lacunocanalicular network architecture

Interactions between Muscle and Bone—Where Physics Meets Biology

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