Menin Functions Critically In Mesenchymal Stem Cells And Osteoblast Progenitors To Promote Bone Development And Maintenance In Vivo
Jad Abi-Rafeh, MSc, Ildi Troka, MSc, Lucie Canaff, PhD, Geoffrey Hendy, PhD, David Goltzman, MD, FACS, FRCSC.
McGill University, Montreal, QC, Canada.
Purpose: Menin, the MEN1 gene product, is expressed in many tissues, including bone, where its function in-vivo remains poorly understood. Methods: Conditional knockout of the Men1 gene in mice was achieved using the Cre-LoxP recombination system: Prx1-Cre;Men1f/f, Osx-Cre;Men1f/f and OC-Cre;Men1f/f represent the deletion of menin in the mesenchymal stem cell, osteoblast progenitor, and mature osteoblast, respectively. Results: Skeletal phenotyping performed at 6 months demonstrated significantly reduced BMD and femur length in the Prx1-Cre; Men1f/f and Osx-Cre; Men1f/f strains. By 3-dimensional micro-CT imaging, all three strains of knockout mice showed decreased trabecular bone volume, altered trabecular structure, and decreased cortical bone thickness. Femur stiffness and ultimate force were reduced in Prx1-Cre; Men1f/f mice as assessed using 3-point bending tests. Primary calvarial osteoblasts of all strains of knockout mice were deficient in mineralization using Alizarin red staining, and exhibited altered gene expression profiles. Osteoblasts from heterozygous (Osx-Cre; Men1+/f) mice were intermediate in this respect. Serum biochemistries were unaffected. By contrast, whereas OC-Cre; Men1f/f mice exhibited reduced numbers of osteoblasts, increased osteocyte density and decreased osteoclast number, Prx1-Cre; Men1f/f and Osx-Cre; Men1f/f mice had marked increases in osteoclast number and unaltered number of osteoblasts. This is consistent with in vitro and in vivo findings of increased RANKL/OPG mRNA ratios supporting increased osteoclastogenesis. Conclusions: We conclude that osteoblast menin plays a crucial role in bone development and maintenance of bone mass in vivo, and may serve as a potential gain-of-function therapeutic target for bone development and regeneration.
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