Osteoporosis and cancer-associated bone disease cause vast morbidity and mortality and are major health threats. The magnitude of these problems has generated considerable interest in understanding the molecular mechanisms that regulate bone density and bone formation. Identification and characterization of the genes that regulate osteoblast proliferation and differentiation have provided new insights into how bone formation occurs. Runx2 is a transcription factor-encoding gene that is necessary for osteoblast development and differentiation. Runx2 transgenes and polymorphic alleles are linked to osteopenia and fracture risk. Runx2 activity is tightly controlled by many cellular, molecular and intermolecular mechanisms. In spite of this vast knowledge, there is still a critical gap concerning how Runx2 activity is negatively controlled. The long-range goal of this work is to understand the molecular mechanisms that control Runx2 activity in osteoblasts for therapeutic purposes. The objective of this application is to determine how the DNA-binding protein and Wnt effector LEF1 regulates Runx2. The central hypothesis is that LEF1 inhibits Runx2-dependent transactivation and osteoblast differentiation. This hypothesis will be tested by pursuing these three Specific Aims: (1) Determining that LEF1 is required for osteoblast maturation with RNA interference and by etopically expressing gain-of-function and loss-of-function LEF1 proteins, (2) Defining the mechanism(s) by which LEF1 represses Runx2 transcriptional activity, and (3) Determining how molecules upstream of LEF1 in the canonical Wnt signaling pathway affect Runx2 transcriptional activity. These results are expected to describe molecular mechanisms from which novel therapeutic interventions for abnormal bone mineral density will be derived. In addition, it is expected that the results will fundamentally advance the fields of transcriptional regulation and osteoblast biology.
| Hoeppner, Luke H; Secreto, Frank J; Razidlo, David F et al. (2011) Lef1DeltaN binds beta-catenin and increases osteoblast activity and trabecular bone mass. J Biol Chem 286:10950-9 |
| Jensen, Eric D; Gopalakrishnan, Rajaram; Westendorf, Jennifer J (2010) Regulation of gene expression in osteoblasts. Biofactors 36:25-32 |
| Hoeppner, Luke H; Secreto, Frank; Jensen, Eric D et al. (2009) Runx2 and bone morphogenic protein 2 regulate the expression of an alternative Lef1 transcript during osteoblast maturation. J Cell Physiol 221:480-9 |
| Jensen, Eric D; Gopalakrishnan, Rajaram; Westendorf, Jennifer J (2009) Bone morphogenic protein 2 activates protein kinase D to regulate histone deacetylase 7 localization and repression of Runx2. J Biol Chem 284:2225-34 |
| Hoeppner, Luke H; Secreto, Frank J; Westendorf, Jennifer J (2009) Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets 13:485-96 |
| Secreto, Frank J; Hoeppner, Luke H; Westendorf, Jennifer J (2009) Wnt signaling during fracture repair. Curr Osteoporos Rep 7:64-9 |
| Kahler, Rachel A; Yingst, Sorcha M C; Hoeppner, Luke H et al. (2008) Collagen 11a1 is indirectly activated by lymphocyte enhancer-binding factor 1 (Lef1) and negatively regulates osteoblast maturation. Matrix Biol 27:330-8 |
| Jensen, Eric D; Niu, Lingling; Caretti, Giuseppina et al. (2008) p68 (Ddx5) interacts with Runx2 and regulates osteoblast differentiation. J Cell Biochem 103:1438-51 |
| Khosla, Sundeep; Westendorf, Jennifer J; Oursler, Merry Jo (2008) Building bone to reverse osteoporosis and repair fractures. J Clin Invest 118:421-8 |
| Jensen, Eric D; Schroeder, Tania M; Bailey, Jaclyn et al. (2008) Histone deacetylase 7 associates with Runx2 and represses its activity during osteoblast maturation in a deacetylation-independent manner. J Bone Miner Res 23:361-72 |
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