title: Core binding factor β of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.
abstract: Core binding factor beta (Cbfβ), the partner protein of Runx family transcription factors, enhances Runx function by increasing the binding of Runx to DNA. Null mutations of Cbfb result in embryonic death, which can be rescued by restoring fetal hematopoiesis but only until birth, where bone formation is still nearly absent. Here, we address a direct role of Cbfβ in skeletal homeostasis by generating osteoblast-specific Cbfβ-deficient mice (Cbfb(Δob/Δob) ) from Cbfb-floxed mice crossed with mice expressing Cre from the Col1a1 promoter. Cbfb(Δob/Δob) mice showed normal growth and development but exhibited reduced bone mass, particularly of cortical bone. The reduction of bone mass in Cbfb(Δob/Δob) mice is similar to the phenotype of mice with haploinsufficiency of Runx2. Although the number of osteoblasts remained unchanged, the number of active osteoblasts decreased in Cbfb(Δob/Δob) mice and resulted in lower mineral apposition rate. Immunohistochemical and quantitative real-time PCR analyses showed that the expression of osteogenic markers, including Runx2, osterix, osteocalcin, and osteopontin, was significantly repressed in Cbfb(Δob/Δob) mice compared with wild-type mice. Cbfβ deficiency also reduced Runx2 protein levels in osteoblasts. The mechanism was revealed by forced expression of Cbfβ, which increased Runx2 protein levels in vitro by inhibiting polyubiquitination-mediated proteosomal degradation. Collectively, these findings indicate that Cbfβ stabilizes Runx2 in osteoblasts by forming a complex and thus facilitates the proper maintenance of bone mass, particularly cortical bone.
authors.affiliation: Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lim
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Park
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Che
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Han
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Jeong
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Clara Yongjoo
authors.initials: CY
authors.lastname: Park
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Hyun-Mo
authors.initials: HM
authors.lastname: Ryoo
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology; D001842:Bone and Bones / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism*
chemical_list: C493693:Cbfb protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; C493716:Runx2 protein, mouse
keywords: BONE MASS; CBFβ; OSTEOBLASTS; POLYUBIQUITINATION; RUNX2