| First Author | Tian F | Year | 2014 |
| Journal | J Bone Miner Res | Volume | 29 |
| Issue | 7 | Pages | 1564-1574 |
| PubMed ID | 24821091 | Mgi Jnum | J:232067 |
| Mgi Id | MGI:5775867 | Doi | 10.1002/jbmr.2275 |
| Citation | Tian F, et al. (2014) Core binding factor beta (Cbfbeta) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation. J Bone Miner Res 29(7):1564-74 |
| abstractText | Core binding factor beta (Cbfbeta) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbfbeta regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbfbeta-deficient (Cbfbeta(f/f) Prx1-Cre) mice were generated to study the role of Cbfbeta in postnatal cartilage and bone development. These mutant mice survived to adulthood but exhibited severe sternum and limb malformations. Sternum ossification was largely delayed in the Cbfbeta(f/f) Prx1-Cre mice and the xiphoid process was noncalcified and enlarged. In newborn and 7-day-old Cbfbeta(f/f) Prx1-Cre mice, the resting zone was dramatically elongated, the proliferation zone and hypertrophic zone of the growth plates were drastically shortened and disorganized, and trabecular bone formation was reduced. Moreover, in 1-month-old Cbfbeta(f/f) Prx1-Cre mice, the growth plates were severely deformed and trabecular bone was almost absent. In addition, Cbfbeta deficiency impaired intramembranous bone formation both in vivo and in vitro. Interestingly, although the expression of Indian hedgehog (Ihh) was largely reduced, the expression of parathyroid hormone-related protein (PTHrP) receptor (PPR) was dramatically increased in the Cbfbeta(f/f) Prx1-Cre growth plate, indicating that that Cbfbeta deficiency disrupted the Ihh-PTHrP negative regulatory loop. Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbfbeta complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbfbeta complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbfbeta-deficient chondrocytes. Taken together, our study reveals not only that Cbfbeta is essential for chondrocyte proliferation and differentiation for the growth and maintenance of the skeleton in postnatal mice, but also that it functions in upregulating Ihh expression to promoter chondrocyte proliferation and osteoblast differentiation, and inhibiting PPR expression to enhance chondrocyte differentiation. |
