Authors
Kyung-Eun Lim PhD, Na-Rae Park BS, Xiangguo Che MD, Min-Su Han PhD, Jae-Hwan Jeong PhD, Shin-Yoon Kim MD, PhD, Clara Yongjoo Park PhD, Haruhiko Akiyama PhD, Jung-Eun Kim PhD, Hyun-Mo Ryoo PhD, Janet L. Stein PhD, Jane B. Lian PhD, Gary S. Stein PhD and Je-Yong Choi DDS, PhD
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 (CbfbΔob/Δob) from Cbfb-floxed mice crossed with mice expressing Cre from the Col1a1 promoter. CbfbΔob/Δob mice showed normal growth and development, but exhibited reduced bone mass, particularly of cortical bone. The reduction of bone mass in CbfbΔob/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 CbfbΔob/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 CbfbΔob/Δob mice compared to 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.