The specific aim of this proposal is to characterize the cis elements and potential transcriptional determinants that confer the tissue-specific expression of type X collagen during chondrocyte hypertrophy. The long-term objective is to understand the molecular regulation of chondrocyte maturation. ? ? Chondrocyte hypertrophy is the terminal stage of chondrocyte differentiation during endochondral ossification of long bone growth and type X collagen is the only known hypertrophic chondrocyte-specific molecular marker. Its deficiency in humans causes Schmid metaphyseal chondrodysplasia (SMCD). Mouse genetic studies show that collagen X deficiency has phenotypic abnormalities partly resemble human SMCD. Until now, cis elements or transcription factors that direct its hypertrophic chondrocyte-specific expression in vivo have not been described. The preliminary data within this proposal show that the 10 kb murine Col10a1 promoter/intron element can direct reporter gene expression throughout the hypertrophic zone. In vivo transgenic, in vitro transfection and in silico analysis of Col10a1 suggests that there are conserved elements within both Col10a1 distal promoter and second intron. We propose to further dissect this 10 kb Col10a1 promoter/intron element and the putative DNA-binding proteins that direct its tissue-specific expression in vivo by using transgenic mice approaches and in vitro by using the MCT cell model of chondrocyte hypertrophy. This is essential for understanding the molecular mechanisms that specify endochondral ossification and that underlie the molecular pathogenesis of skeletal dysplasias like those involving type X collagen. ? ?
| Li, Feifei; Lu, Yaojuan; Ding, Ming et al. (2012) Putative function of TAP63? during endochondral bone formation. Gene 495:95-103 |
| Ding, Ming; Lu, Yaojuan; Abbassi, Sam et al. (2012) Targeting Runx2 expression in hypertrophic chondrocytes impairs endochondral ossification during early skeletal development. J Cell Physiol 227:3446-56 |
| Li, Feifei; Lu, Yaojuan; Ding, Ming et al. (2011) Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer. J Bone Miner Res 26:2899-910 |
| Zheng, Qiping; Keller, Bettina; Zhou, Guang et al. (2009) Localization of the cis-enhancer element for mouse type X collagen expression in hypertrophic chondrocytes in vivo. J Bone Miner Res 24:1022-32 |
