Chondrocyte-specific Knockout of Cbfβ Reveals the Indispensable Function of Cbfβ in Chondrocyte Maturation, Growth Plate Development and Trabecular Bone Formation in Mice

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 (Cbf beta) in postnatal cartilage development and endochondral bone formation, we generated chondrocyte-specific Cbf beta-deficient mice (Cbf beta f/fCol2 alpha 1-Cre mice) using floxed alleles of Cbf beta (Cbf beta f/f) and Cre driven by the Collagen 2 alpha 1 promoter (Col2 alpha 1-Cre). Cbf beta f/fCol2 alpha 1-Cre mice evaded developmental and newborn lethality to survive to adulthood and displayed severe skeletal malformation. Cbf alpha f/fCol2 alpha 1-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 Cbf beta f/fCol2 alpha 1-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. Cbf beta deficiency led to down-regulation of chondrocyte-regulating genes [i.e, patched (Ptc1), Cyclin DI 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 Cbf beta 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 Cbf beta, was critical to trabecular bone morphogenesis. Significantly, these findings provide insight into the role of Cbf beta in postnatal skeletogenesis, which may assist in the development of new therapies for osteoporosis.