Osteoblast Biology and Transcriptional Regulation - Jennifer Westendorf

Overview

My laboratory focuses on the molecular mechanisms whereby the transcription factor, Runx2, regulates gene expression. Runx2 is essential for osteoblast development and bone formation. It also contributes to bone disease caused by metastatic breast and prostate tumors.

Runx2 is both an activator and repressor of gene expression. We are defining mechanisms whereby Runx2 represses transcription. Thus far, we have identified four histone deacetylases (HDACs) that act as co-repressors for Runx2. Future directions for this project are to:

• Define the roles of specific HDACs in osteoblast development;
• Identify signaling pathways that affect the ability of HDACs to bind Runx2; and
• Determine if HDAC suppression affects bone formation and cancer-associated bone disease in animal models.

HDAC inhibitors are currently in clinical trials as anti-cancer treatments. These studies will contribute to our understanding of how HDAC inhibitors will affect metastatic tumor growth in bones and how HDAC inhibitors will affect bone formation.

The other major project in the laboratory focuses on another transcription factor, Lef1. Lef1 is a nuclear effecter of the Wnt signaling pathway, which supports osteoblast proliferation and survival. We showed that Lef1 interacts with Runx2 and thus for the first time linked two important molecular pathways in osteoblasts. We also showed that Lef1 suppression accelerates osteoblast differentiation, while Lef1 overexpression suppresses osteoblast maturation. We are now working to define the role of Lef1 and its alterative isoforms in osteoblasts in vivo. Wnts are being considered as possible bone anabolic agents; however, Wnts are known oncogenes. By understanding the molecular mechanisms of a Wnt effecter molecule (Lef1), we are gaining additional knowledge about the pathway and about bone formation.