Osteoblast Menin Regulates Bone Mass In Vivo [Molecular Bases of Disease]

December 23rd, 2014 by Kanazawa, I., Canaff, L., Abi Rafeh, J., Angrula, A., Li, J., Riddle, R. C., Boraschi-Diaz, I., Komorova, S. V., Clemens, T. L., Murshed, M., Hendy, G. N.

Menin, the product of the multiple endocrine neoplasia type 1 (Men1) tumor suppressor gene, mediates the cell proliferation and differentiation actions of transforming growth factor-beta (TGF-β) ligand family members. In vitro, menin modulates osteoblastogenesis and osteoblast differentiation promoted and sustained by bone morphogenetic protein-2 (BMP-2) and TGF-β, respectively. To examine the in vivo function of menin in bone, we conditionally inactivated Men1 in mature osteoblasts by crossing osteocalcin (OC)-Cre mice with floxed Men1 (Men1f/f) mice to generate mice lacking menin in differentiating osteoblasts (OC-Cre;Men1f/f mice). These mice displayed significant reduction in bone mineral density, trabecular bone volume and cortical bone thickness compared to control littermates. Osteoblast and osteoclast number, as well as mineral apposition rate (MAR) were significantly reduced, whereas osteocyte number was increased. Primary calvarial osteoblasts proliferated more quickly, but had deficient mineral apposition and alkaline phosphatase activity. While the mRNA expression of osteoblast marker and cyclin-dependent kinase inhibitor genes were all reduced, that of cyclin dependent kinase, osteocyte marker and pro-apoptotic genes were increased in isolated Men1 knockout osteoblasts compared to controls. In contrast to the knockout mice, transgenic mice overexpressing a human menin cDNA in osteoblasts driven by the 2.3-kb Col1a1 promoter, showed a gain of bone mass relative to control littermates. Osteoblast number and MAR were significantly increased in the Col1a1-Menin-Tg mice. Therefore, osteoblast menin plays a key role in bone development, remodeling and maintenance.