title: Osteoblast menin regulates bone mass in vivo.
abstract: 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-β (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 (Men1(f/f)) mice to generate mice lacking menin in differentiating osteoblasts (OC-Cre;Men1(f/f) mice). These mice displayed significant reduction in bone mineral density, trabecular bone volume, and cortical bone thickness compared with control littermates. Osteoblast and osteoclast number as well as mineral apposition rate were significantly reduced, whereas osteocyte number was increased. Primary calvarial osteoblasts proliferated more quickly but had deficient mineral apposition and alkaline phosphatase activity. Although 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 knock-out osteoblasts compared with controls. In contrast to the knock-out 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 mineral apposition rate were significantly increased in the Col1a1-Menin-Tg mice. Therefore, osteoblast menin plays a key role in bone development, remodeling, and maintenance.
authors.affiliation: From the Departments of Medicine.
authors.forename: Ippei
authors.initials: I
authors.lastname: Kanazawa
authors.affiliation: From the Departments of Medicine.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.affiliation: Physiology.
authors.forename: Jad
authors.initials: J
authors.lastname: Abi Rafeh
authors.affiliation: From the Departments of Medicine.
authors.forename: Aarti
authors.initials: A
authors.lastname: Angrula
authors.affiliation: Dentistry.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Veterans Administration Medical Center, Baltimore, Maryland 21201.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Riddle
authors.affiliation: Dentistry.
authors.forename: Iris
authors.initials: I
authors.lastname: Boraschi-Diaz
authors.affiliation: Dentistry.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Veterans Administration Medical Center, Baltimore, Maryland 21201.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.affiliation: From the Departments of Medicine, Dentistry.
authors.forename: Monzur
authors.initials: M
authors.lastname: Murshed
authors.affiliation: From the Departments of Medicine, Physiology, Human Genetics, and Calcium Research Laboratory, and Hormones and Cancer Research Unit, Royal Victoria Hospital, McGill University, Montreal, Quebec H3A 1A1, Canada, geoffrey.hendy@mcgill.ca.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015519:Bone Density; D001846:Bone Development / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta
keywords: Bone; Bone Morphogenetic Protein (BMP); Gene Knockout; Menin; Mouse; Osteoblast; Osteoclast; Osteocyte; Transforming Growth Factor β (TGF-B)