Renny Franceschi, Ph.D.

Dr. Franceschi’s laboratory is studying signals regulating the formation and functioning of osteoblasts, cells that produce and mineralize the extracellular matrix of bone, and is applying this knowledge to regenerate mineralized tissues for eventual clinical use. Additional studies are examining the role of bone-related factors in the development and metastasis of prostate cancer to bone. We use a variety of molecular approaches in our studies and make extensive use of cell/organ culture and transgenic mouse models.
Specific projects include:

1) Studies to elucidate the mechanism of gene regulation in bone with emphasis on Runx2, a bone-specific transcription factor that controls differentiation of osteoblasts from mesenchymal stem cells. Runx2 is essential for bone formation and induction of the osteoblast lineage. We showed that Runx2 is activated by MAP kinase (ERK and p38)-mediated phosphorylation and are examining how phosphorylation induces epigenetic changes to alter chromatin architecture and osteoblast-specific gene expression.

2) Analysis of signals involved in mesenchymal stem cell lineage switching between osteoblasts and adipocytes and regulation of these signals by mechanical loading of the skeleton. Lack of weigh-bearing exercise is a major cause of osteoporosis and bone loss. We identified a specific signaling pathway in bone that is activated by mechanical loading and showed how this pathway can push stem cells in bone marrow to make more bone and less marrow fat. This pathway, which involves reciprocal control of Runx2 and PPAR transcription factors, may be an important therapeutic target for increasing bone mass in osteoporosis.

3) Development of gene therapy approaches to stimulate bone regeneration through the controlled expression of BMPs and other morphogenic compounds. Methods are being developed that use focused ultrasound to control the delivery of growth factors to specific locations within regenerating tissues. These methods may have wide applications in regenerative medicine where patterned delivery of growth factors is critical to produce new tissues of defined shape and size.

4) Elucidation of mechanism/s of bone biomineralization and analysis of the role of circadian cycles in this process. Bone is subject to circadian regulation with most new bone formation occurring during the resting phase of the light/dark cycle. Cyclical bone mineralization can be measured in real time using Raman spectroscopy. Studies are using organ culture and transgenic approaches to examine the relationship between cyclical activation of clock genes and bone formation pathways.

5) Studies on the role of Runx2 in prostate cancer initiation and metastasis. Runx2 is abnormally expressed in many cancers including prostate, breast, lung and melanomas. We developed a phospho-Runx2 antibody that specifically stains prostate cancer cells, but not normal prostate tissue, and showed that the intensity of antibody staining correlates with tumor severity and metastasis. We think P-Runx2 may be involved in the formation of prostate cancer stem cells, a tumor fraction that is particularly resistant to chemotherapy and necessary for tumor growth and metastasis. Thus, Runx2 may be an important target for therapy since its inhibition would be predicted to make tumors more vulnerable to chemotherapeutics.