Cbfß deletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfß required for skeletal development.

ABSTRACT

The pathogenesis of cleidocranial dysplasia (CCD) as well as the specific role of core binding factor ß (Cbfß) and the Runt-related transcription factor (RUNX)/Cbfß complex in postnatal skeletogenesis remain unclear. We demonstrate that Cbfß ablation in osteoblast precursors, differentiating chondrocytes, osteoblasts, and odontoblasts via Osterix-Cre, results in severe craniofacial dysplasia, skeletal dysplasia, abnormal teeth, and a phenotype recapitulating the clinical features of CCD. Cbfß(f/f)Osterix-Cre mice have fewer proliferative and hypertrophic chondrocytes, fewer osteoblasts, and almost absent trabecular bone, indicating that Cbfß may maintain trabecular bone formation through its function in hypertrophic chondrocytes and osteoblasts. Cbfß(f/f)Collagen, type 1, alpha 1 (Col1α1)-Cre mice show decreased bone mineralization and skeletal deformities, but no radical deformities in teeth, mandibles, or cartilage, indicating that osteoblast lineage-specific ablation of Cbfß results in milder bone defects and less resemblance to CCD. Activating transcription factor 4 (Atf4) and Osterix protein levels in both mutant mice are dramatically reduced. ChIP assays show that Cbfß directly associates with the promoter regions of Atf4 and Osterix. Our data further demonstrate that Cbfß highly up-regulates the expression of Atf4 at the transcriptional regulation level. Overall, our genetic dissection approach revealed that Cbfß plays an indispensable role in postnatal skeletal development and homeostasis in various skeletal cell types, at least partially by up-regulating the expression of Atf4 and Osterix. It also revealed that CCD may result from functional defects of the Runx2/Cbfß heterodimeric complex in various skeletal cells. These insights into the role of Cbfß in postnatal skeletogenesis and CCD pathogenesis may assist in the development of new therapies for CCD and osteoporosis.