Areas of Interest
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.
Honors & Awards
1998,2004 Mentor to Am. Society for Bone and Mineral Research Young Investigator Awardees, Dr. G. Xiao and C. Ge
2001 President, IADR Mineralized Tissues Group
2006 Chair of the Skeletal Biology, Structure and Regeneration Study Section at the Center for Scientific Review at NIH
2008 Distinguished Scientist Award for Basic Research in Biological Mineralization, International Association for Dental Research
Roca H and Franceschi RT. Analysis of Transcription Factor Interactions in Osteoblasts by Competitive Chromatin Immunoprecipitation. Nucleic Acids Res. 36:1723-1730, 2008 PubMed ID #18263612. PMCID: PMC2275161
Ge C, Jiang D, Xiao G, Roca H and Franceschi RT. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J Biol Chem 284:32533-32543, 2009. PMID: 19801668 PMCID: PMC2781667
Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi RT, Guan K, Krebsbach P and Wang CY. Inhibition of IKK in differentiated osteoblasts enhances postnatal bone formation and prevents bone loss in osteoporosis. Nature Medicine 15:682-689, 2009. PMID: 19448637 PMCID: PMC2768554
Yu S, R. Franceschi, M. Luo, J. FAN, D. Jiang, H. Cao, Y. Lai, J. Zhang, K. Patrene, K. Hankenson, G. Roodman, G. Xiao. Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One. 2009 Oct 23;4(10):e7583. doi:10.1371/journal.pone.0007583, 2009. PMID: 19851510 PMCID: PMC2762317
Li Y, Ge C and Franceschi RT. Differentiation-dependent association of phosphorylated extracellular signal-regulated kinase with the chromatin of osteoblast-related genes. J Bone Miner Res. 2010 Jan;25(1):154-63. PMID: 19580458 PMCID: PMC3153324
Yang S, Xu H, Yu S, Cao H, Fan J, Ge C, Franceschi RT, Dong H and Xiao G. FOXO1 mediates IGF1/insulin regulation of osteocalcin expression by antagonizing RUNX2 in osteoblasts. J Biol Chem 286:19149-19158, 2011. PMCID: PMC3099728
Ge C, Yang Q, Zhao G, Yu H, Kirkwood K and Franceschi RT. Interactions between ERK1/2 and p38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res 551,2012. PMID: 22072425
Li Y, Ge C, Long JP. Begun DL, Rodriguez JA, Goldstein SA and Franceschi Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor. J Bone Miner Res 27:538-551, 2012. PMCID: PMC3532028
McEldery J-D, Zhao G, Khmaladze A, Wilson CG, Franceschi RT and Morris MD. Tracking Circadian Rhythms of Bone Mineral Deposition in Murine Calvarial Organ Cultures. J Bone Miner Res 28:1846-1854, 2013. PMID: 23505073 PMCID: PMC3720727
Wilson CG, Martín-Saavedra FM, Vilaboa-Díaz N, Franceschi RT. Advanced BMP Gene Therapies for Temporal & Spatial Control of Bone Regeneration, J Dental Res-Crit Rev Oral Biol Med 92:409-417, 2013. PMID: 23539558 PMCID: PMC3627508
Wilson, CG, Martín-Saavedra FM, Padilla F, Fabiilli ML, Zhang M, Baez AM, Christopher J. Bonkowski CJ, Kripfgans OD, Voellmy R, Vilaboa N, Fowlkes JB, Franceschi RT. Patterning Expression of Regenerative Growth Factors Using High Intensity Focused Ultrasound. Tissue Engineering Part C Methods-March 11, 2014.
Ge C, Zhao G, Li Y, Li H, Zhao X, Pannone G, Bufo P, Santoro A, Sanguedolce F, Tortorella S, Mattoni M, Papagerakis S, Keller ET and Franceschi RT. Role of Runx2 Phosphorylation in Prostate Cancer and Association with Metastatic Disease. Submitted, Oncogene