期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：23
页码：8482-8487
DOI：10.1073/pnas.1310617111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The pathogenesis of cleidocranial dysplasia (CCD) as well as the specific role of core binding factor {beta} (Cbf{beta}) and the Runt-related transcription factor (RUNX)/Cbf{beta} complex in postnatal skeletogenesis remain unclear. We demonstrate that Cbf{beta} 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. Cbf{beta}f/fOsterix-Cre mice have fewer proliferative and hypertrophic chondrocytes, fewer osteoblasts, and almost absent trabecular bone, indicating that Cbf{beta} may maintain trabecular bone formation through its function in hypertrophic chondrocytes and osteoblasts. Cbf{beta}f/fCollagen, type 1, alpha 1 (Col11)-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 Cbf{beta} 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 Cbf{beta} directly associates with the promoter regions of Atf4 and Osterix. Our data further demonstrate that Cbf{beta} highly up-regulates the expression of Atf4 at the transcriptional regulation level. Overall, our genetic dissection approach revealed that Cbf{beta} 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/Cbf{beta} heterodimeric complex in various skeletal cells. These insights into the role of Cbf{beta} in postnatal skeletogenesis and CCD pathogenesis may assist in the development of new therapies for CCD and osteoporosis.
