Murine models for human bone disease

Abstract

Osteoporosis is a metabolic bone disease that promotes bone weakens. It is a world health problem affecting one in three women and one in five men. Bisphosphonates are the drug most used to treat this disease, although after a long period the action reverses prompting bones to fracture. There is research required to solve this osteoporosis and long-term treatment fragility. On this basis we aim to develop a new strategy to study osteoporotic bones through murine osteoporosis models, in a new technique to evaluate bone quality in nanoscale, strategies to perform biomechanical analyses, an osteopenia model and a mice model to study the deleterious effect of bisphosphonate delivered for long-term. It was performed in four studies. First, a group of sham-operated (N=7) mice was compared to ovariectomized mice (n=7) to evaluate osteoporotic bone through Raman Spectroscopic in vivo. Secondly, to find bone fragility through biomechanical parameters in murine models ex vivo a group of mice sham-operated (n=7) and ovariectomized (n=7); rats sham-operated (n=5) and ovariectomized (n=6) had the femurs loaded to fail in a physiological approach and in a constrained and unconstrained manner. The influence of the weight gain on results were discussed through two ways to normalize it. Third, an osteopenia model through disuse was performed to evaluate how the tibia compartments (cortical, trabecula and shape) behave after 5 (n=5), 35 (n=4), 65 (n=5) and 95 (n=3) days of disuse due to sciatic neurectomy. Finally, seeking for the deleterious effect of Bisphosphonate, three groups of mice were formed: control (n = 7), ovariectomized (n = 7) and ovariectomized add to the administration of Ibandronate. After euthanasia, the femurs were collected for biomechanical tests on the femoral neck and the tibiae were used for analysis of architecture, mass and geometry. In conclusion, first, Raman Spectroscopic showed a diminishment in bone quality of osteoporotic bones as a result of decrease calcium and glycosaminoglycans and increase lipids content. Secondly, it is possible to load to fail murine bones to find osteoporosis weakens, but it depends on test sensibility (constrained and unconstrained) and a normalization of the results through body mass is required. Third, bones with osteopenia reabsorbed each compartment in a different way where trabecula starts first but required more time to reach a plateau than cortical. And finally, ovariectomy combined with bisphosphonate for long term promote a different fracture padrone on femora neck and a deleterious effect on tibia shape.