An Experimental And Computational Analysis Of Mouse Femur Biomechanics Following The Deletion Of Menin In The Osteoblast Lineage
Jad Abi-Rafeh, MSc, MD, CM (c), Meisam Asgari, PhD, Ahmed Moussa, PhD, Geoffrey Hendy, PhD, Damiano Pasini, PhD, David Goltzman, MD, FACS, FRCSC.
McGill University, Montreal, QC, Canada.
Purpose:Recent studies have established the critical role of menin in the development and maintenance of bone mass by regulating osteoblast, osteoclast and osteocyte function in vivo. In the present study, a combined approach of experimentation and simulation is pursued to provide prediction and comparison of elastic responses to physiological loading of bone in mice harboring a deletion of the Men1 gene in the osteoblast lineage.Methods: The Cre-LoxP recombination system was used; Prx1-Cre; Men1f/f represent mice in which the MEN1gene was inactivated in the mesenchymal stem cells (KO), and Men1f/f represent wild type (WT) controls. Male mice were sacrificed and analyzed at 9 months of age. Results: Major macroscopic geometrical changes were observed in the femora of KO mice, most notably, a significant decrease in length and changes in mid-metaphyseal cross-sectional area. Micro-CT imaging demonstrated marked reductions in trabecular bone volume, altered cortical thickness, and a decrease in trabecular number. Three-point bending tests were conducted to evaluate macroscopic elastic-plastic behavior demonstrating a 30% reduction in bone stiffness in menin-deficient mice. Atomic Force Microscopy was used to examine the elasticity of both cortical and trabecular bone in the longitudinal and transverse directions independently; KO mice demonstrated significant decreases in elasticity of both bone types. Micro-CT 3D solid model reconstructions were assessed via finite element analysis simulation. Bone local mineral density was used to obtain its local elastic modulus. A benchmark problem was then assessed on the reconstructed 3D models, and relevant metrics evaluated and compared. Results indicate that the flexural rigidity of the KO femurs is significantly lower than that of WT following the deletion of the Men1 gene in the osteoblast lineage. Conclusions:The experimental and computational analyses employed in this study may be applied for the phenotypic characterization of murine models in bone physiological studies. Menin plays a critical role in the development and maintenance of bone mass and may thus serve as a potential gain-of-function therapeutic target in bone development and regeneration.
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