title: Chondrocyte-specific knockout of Cbfβ reveals the indispensable function of Cbfβ in chondrocyte maturation, growth plate development and trabecular bone formation in mice.
abstract: Despite years of research into bone formation, the mechanisms by which transcription factors specify growth plate development and trabecular bone formation remain unclear and the role of hypertrophic chondrocytes in trabeculae morphogenesis is controversial. To study the role of Core binding factor beta (Cbfβ) in postnatal cartilage development and endochondral bone formation, we generated chondrocyte-specific Cbfβ-deficient mice (Cbfβf/fCol2α1-Cre mice) using floxed alleles of Cbfβ (Cbfβf/f) and Cre driven by the Collagen 2α1 promoter (Col2α1-Cre). Cbfβf/fCol2α1-Cre mice evaded developmental and newborn lethality to survive to adulthood and displayed severe skeletal malformation. Cbfβf/fCol2α1-Cre mice had dwarfism, hypoplastic skeletons, defective bone mineralization, shortened limbs, shortened sternum bodies, and un-calcified occipital bones and hyoid bones. In the long bone cartilage, the resting zone was elongated, and chondrocyte proliferation and hypertrophy were impaired in Cbfβf/fCol2α1-Cre mice, which led to deformation of the growth plates. Primary spongiosa formation was delayed, diaphysis was shortened and trabecular bone formation was almost absent in the mutant mice. In addition, lamellar bone formation in the secondary spongiosa was also impaired. However, osteoclast formation in the trabecular bone was not affected. Cbfβ deficiency led to down-regulation of chondrocyte-regulating genes [i.e, patched (Ptc1), Cyclin D1 and Indian hedgehog (Ihh)] in the cartilage. Interestingly, the expression of Runx2 and Runx3 was not changed in the cartilage of the mutants. Collectively, the results revealed that Cbfβ is crucial for postnatal skeletal development and endochondral bone formation through its function in growth plate development and chondrocyte proliferation and differentiation. This study also revealed that chondrocyte maturation, mediated by Cbfβ, was critical to trabecular bone morphogenesis. Significantly, these findings provide insight into the role of Cbfβ in postnatal skeletogenesis, which may assist in the development of new therapies for osteoporosis.
authors.affiliation: 1. Institute of Genetics, Life Science College, Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China. ; 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Mengrui
authors.initials: M
authors.lastname: Wu
authors.affiliation: 1. Institute of Genetics, Life Science College, Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China. ; 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.affiliation: 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 1. Institute of Genetics, Life Science College, Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China. ; 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Jules
authors.affiliation: 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McConnell
authors.affiliation: 3. Department of Cell, Development, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
authors.affiliation: 1. Institute of Genetics, Life Science College, Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Shao
authors.affiliation: 2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000166:cytology* / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D010012:Osteogenesis / Q000502:physiology
chemical_list: D050658:Core Binding Factor beta Subunit
keywords: Cbfβ; Indian hedgehog (Ihh); Runx; chondrocyte proliferation and hypertrophy; endochondral bone formation.; skeletal development