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

ABSTRACT: In vivo, tibial loading in mice is increasingly used to study bone adaptation and mechanotransduction. To achieve standardized and defined experimental conditions, loading parameters and animal-related factors must be considered when performing in vivo loading studies. In this review, we discuss these loading and animal-related experimental conditions, present methods to assess bone adaptation, and suggest reporting guidelines. This review originated from presentations by each of the authors at the workshop "Developing Best Practices for Mouse Models of In Vivo Loading" during the Preclinical Models Section at the Orthopaedic Research Society Annual Meeting, San Diego, CA, March 2017. Following the meeting, the authors engaged in detailed discussions with consideration of relevant literature. The guidelines and recommendations in this review are provided to help researchers perform in vivo loading experiments in mice, and thus further our knowledge of bone adaptation and the mechanisms involved in mechanotransduction. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:233-252, 2020.

SUBMITTER: Main RP

PROVIDER: S-EPMC9344861 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Main Russell P RP Shefelbine Sandra J SJ Meakin Lee B LB Silva Matthew J MJ van der Meulen Marjolein C H MCH Willie Bettina M BM

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20191023 2

In vivo, tibial loading in mice is increasingly used to study bone adaptation and mechanotransduction. To achieve standardized and defined experimental conditions, loading parameters and animal-related factors must be considered when performing in vivo loading studies. In this review, we discuss these loading and animal-related experimental conditions, present methods to assess bone adaptation, and suggest reporting guidelines. This review originated from presentations by each of the authors at ...[more]

PMID: 31508836

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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 μϵ and a transition from lamellar-woven bone near -2,000 μϵ. 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 μϵ 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:Osteolytic bone lesions, which develop in many metastatic breast cancer patients, impair bone integrity and lead to adverse skeletal related events that are difficult to treat and sometimes fatal. Moderate mechanical loading has been shown to suppress osteolysis in young mice with breast cancer. In this study, we aimed to investigate the dose-dependent effects of mechanical loading on protecting the integrity of adult skeletons with breast cancer. Localized tibial loading and aerobic treadmill running with three levels of varying intensity were tested in a syngeneic mammary tumor bone metastasis model. Adult C57BL/6J female mice (14-week-old, N = 88 mice) received intra-tibial injections of Py8119 triple-negative murine breast cancer cells or PBS and underwent 4 to 5 weeks of exercise or acted as sedentary/non-loaded controls. The bone structure was monitored longitudinally with weekly in vivo micro-computed tomography imaging, while the cellular responses in bone and marrow were examined using immunohistochemistry. Moderate treadmill running (16 m/min, 50 min/day, 5 days/week, and 5 weeks) and tibial loading (4.5 N, 630 με, 4 Hz, 300 cycles/day, 5 days/week, and 4 weeks) suppressed tumor-induced bone destruction, as evaluated by full-thickness perforation of tibial cortex and the volume of osteolytic lesions in the cortex. In contrast, tibial loading at higher magnitude (8 N, 1100 με) induced woven bone and accelerated bone destruction, compared with the non-loaded controls. The three exercise regimens differentially affected osteocyte apoptosis, osteocyte hypoxia, osteoclast activity, bone marrow vasculature, and tumor proliferation. In conclusion, the relationship between exercise intensity and the risk of breast cancer-induced osteolysis was found to follow a J-shaped curve in a preclinical model, suggesting the need to optimize exercise parameters in order to harness the skeletal benefits of exercise in metastatic breast cancers.

Project description:The relationship between osteogenesis and angiogenesis is complex. Normal bone development requires angiogenesis, mediated by vascular endothelial growth factor A (VEGFA). Studies have demonstrated through systemic inhibition or genetic modification that VEGFA is indispensable for several types of bone repair, presumably via its role in supporting angiogenesis. But a direct role for VEGFA within osteoblasts, in the absence of angiogenesis, has also been suggested. To address the question of whether VEGFA from osteoblasts supports bone formation directly, we applied anabolic loading to induce lamellar bone formation in mice, a process shown to be independent of angiogenesis. We hypothesized that VEGFA from osteoblasts is required for lamellar bone formation. To test this hypothesis, we applied axial tibial compression to inducible Cre/LoxP mice from three lines. Vegfafl/fl mice were crossed with Ubiquitin C (UBC), Osterix (Osx) and Dentin-Matrix Protein 1 (DMP1) Cre-ERT2 mice to target all cells, (pre)osteoblast-lineage cells, and mature osteoblasts and osteocytes, respectively. Genotype effects were determined by comparing control (Vegfafl/fl) and Cre+ (VegfaΔ) mice for each line. At 5 months of age tamoxifen was injected for 5 days followed by a 3-week clearance prior to loading. Female and male mice (N = 100) were loaded for 5 days to peak forces to engender -3100 με peak compressive strain and processed for dynamic histomorphometry (day 12). Percent MS/BS increased 20-70 % as a result of loading, with no effect of genotype in Osx or Dmp1 lines. In contrast, the UBC groups had a significant decrease in relative periosteal BFR/BS in VegfaΔ vs. Vegfafl/fl mice. The UBC line did not have any cortical bone phenotype in non-loaded femurs. In summary, dynamic histomorphometry data confirmed that tibial loading induces lamellar bone formation. Contrary to our hypothesis, there was no decrease in loading-induced bone formation in the Osx or Dmp1 lines in the absence of VEGFA. There was a decrease in bone formation in the UBC line where all cells were targeted. This result indicates that VEGFA from a non-osteoblast cell source supports loading-induced lamellar bone formation, although osteoblast/osteocyte VEGFA is dispensable. These findings support a paracrine model whereby non-osteoblast VEGFA supports lamellar bone formation, independent of angiogenesis.

Dataset Information

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

Publications

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

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