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Menin, the <jats:italic>MEN1<\/jats:italic> gene product, is expressed in many tissues, including bone, where its function remains elusive. We conditionally inactivated menin in mesenchymal stem cells (MSCs) using paired\u2010related homeobox 1 (Prx1)\u2010Cre and compared resultant skeletal phenotypes of <jats:italic>Prx1\u2010Cre<\/jats:italic>;<jats:italic>Men1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup> menin\u2010knockout mice (KO) and wild\u2010type controls using in vivo and in vitro experimental approaches and mechanics simulation. Dual\u2010energy X\u2010ray absorptiometry demonstrated significantly reduced bone mineral density, and 3\u2010dimensional micro\u2010CT imaging revealed a decrease in trabecular bone volume, altered trabecular structure, and an increase in trabecular separation in KO mice at 6 and 9\u2009months of age. Numbers of osteoblasts were unaltered, and dynamic histomorphometry demonstrated unaltered bone formation; however, osteoclast number and activity and receptor activator of NF\u2010\u03baB ligand\/osteoprotegerin (RANKL\/OPG) mRNA profiles were increased, supporting increased osteoclastogenesis and bone resorption. In vitro, proliferative capabilities of bone marrow stem cells and differentiation of osteoblasts and mineralization were unaltered; however, osteoclast generation was increased. Gross femur geometrical alterations observed included significant reductions in length and in mid\u2010metaphyseal cross\u2010sectional area. Atomic force microscopy demonstrated significant decreases in elasticity of both cortical and trabecular bone at the nanoscale, whereas three\u2010point bending tests demonstrated a 30% reduction in bone stiffness; finite element analysis showed morphological changes of the femur microgeometry and a significantly diminished femur flexural rigidity. The biomechanical results demonstrated the detrimental outcome of the accelerated osteoclastic bone resorption. Our studies have a twofold implication; first, <jats:italic>MEN1<\/jats:italic> deletion from MSCs can negatively regulate bone mass and bone biomechanics, and second, the experimental and computational biomechanical analyses employed in the present study should be applicable for improved phenotypic characterization of murine bone. Furthermore, our findings of critical menin function in bone may underpin the more severe skeletal phenotype found in hyperparathyroidism associated with loss\u2010of\u2010function of the <jats:italic>MEN1<\/jats:italic> gene. \u00a9 2022 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10622","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T09:43:35Z","timestamp":1647164615000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis"],"prefix":"10.1093","volume":"6","author":[{"given":"Jad","family":"Abi\u2010Rafeh","sequence":"first","affiliation":[{"name":"Department of Medicine McGill University and McGill University Health Centre  Montreal 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