Many bone diseases are caused by or are related to defects in osteoblast and chondrocyte function. An understanding of the mechanisms by which bone and cartilage formation is controlled is therefore critical to understanding the pathogenesis of these bone diseases and to determine the molecular targets for development of new therapies for their treatment. The long-term goal of this proposal is for the Principal Investigator (PI) to develop an independent career focused on investigating the regulatory mechanisms of osteoblast and chondrocyte function and developing novel therapeutic strategies to improve outcomes in bone-related pathologic situations. In this Independent Scientist Award (K02) application, the candidate outlines a plan that will enable him achieve this objective. The PI will use the K02 to acquire additional skills in bone histology, histomorphometry, and in vitro and in vivo chondrocyte research and Drs. Brendan Boyce and Regis O'Keefe will provide an excellent support and training experience for the candidate in the 'state of the art' institutional facilities at University of Rochester. The focus of the research will be on the regulation of bone and cartilage formation by the ubiquitin-proteasome pathway. Specifically, the aims will encompass examining the regulatory mechanisms of Runx2 and BMP signaling proteins by the E3 ubiquitin ligase Smurfl. Smurf 1 is a member of the Meet domain family of E3 ubiquitin ligases and has been found to interact with BMP-activated Smads 1 and 5 and induce their degradation (Zhu et al., 1999). In preliminary studies, we have demonstrated for the first time that Smurfl induces Runx2 degradation through an ubiquitin-proteasome pathway (Zhao et al., 2003). Smad6 interacts with Runx2 and mediates Smurfl-induced Ruhx2 degradation (Shen et al., 2005). Smurfl inhibits osteoblast differentiation in vitro and postnatal bone formation in vivo (Zhao et al., 2004). In the proposed studies, we will investigate roles of Smurfl in bone formation and chondrocyte maturation by analyzing the Col11a1-Smurfl, Col1a1-mSmurf1 and Col2a1-Smurfl transgenic mice which have been generated in the Pi's lab recently. In these mice, expression of Smurfl or mSmurfl transgene is targeted specifically to osteoblasts and chondrocytes using the tissue-specific co!1a1 and co!2a1 promoters. The underlying hypothesis for the proposed studies is that Smurfl is an important regulatory molecule for Runx2 and Smadl function and plays a specific role in osteoblast and chondrocyte differentiation.
The specific aims of the project are: 1) to determine the specific effect of Smurfl on bone formation during bone coupling; and 2) to determine the role of Smurfl in chondrocyte differentiation and maturation. Two working hypotheses will be tested: 1) Smurfl inhibits bone formation during bone coupling in adult mice; and 2) Smurfl is a negative regulator in chondrocyte differentiation and maturation. The results from these studies will provide insights into the mechanisms of Smurfl in regulation of the maturational program of osteoblasts and chondrocytes. ? ? ? ?
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