Investigators

Summary

Dr. Deborah Galson's laboratory is focused on two main areas:

(1) Determining the mechanism by which multiple myeloma (MM) cells reduce bone formation via suppression of the differentiation capacity of osteoblast progenitor cells in a manner that persists even after removal of the myeloma cells. These MM-altered bone marrow stromal cells also enhance osteoclastogenesis and microenvironmental support of myeloma growth. We have shown that myeloma cells induce the upregulation of expression of the transcriptional repressor Gfi1 in osteoblast precursor cells and that Gfi1 has a role in repressing Runx2, the key osteoblast transcription factor. We are currently investigating the mechanisms by which Gfi1 represses Runx2; MM cells and TNF-alpha/IL-7 regulate Gfi1 expression and activity; and roles for Gfi1 in MM cells and osteoclasts. Our preliminary data suggests that Gfi1 may prove to be a useful 3-way therapeutic target in MM bone disease. We are also expanding these studies into other cancer-induced bone disease models and into inflammatory diseases that cause bone formation suppression.

(2) Determining the mechanism by which measles virus nucleocapsid protein (MVNP) activates cellular genes and alters osteoclast differentiation. MVNP has been shown to be able to induce a Pagetic phenotype when transduced into osteoclast precursors and there is increasing evidence that it can play a role in the development of Paget's disease. Understanding the mechanisms involved may aid in developing additional treatments for Paget's disease as well as increase our understanding of how viral proteins alter cells. We have made the important discovery that MVNP signals through the IKK family members TBK1 and IKKepsilon to increase IL-6, a key player in creating the pagetic microenvironment. We are also studying MVNP regulation of C/EBPbeta and FoxO proteins, as well as autophagy, in generating aberrant osteoclasts. We have found that MVNP alters both the level of C/EBPbeta expression as well as the translation regulation of the C/EBPbeta LAP/LIP isoforms ratio. MVNP also alters the regulation of FoxO1 cellular localization, preventing nuclear localization, which increases autophagy, Further, MVNP alters the stability of FoxO3a, leading to rapid degradation and loss of SIRT1 expression, which thereby increases NF-kappaB activity. We are expanding the investigation of TBK1 and IKKepsilon signal transduction into other disease models that elevate osteoclasts including cancer-induced bone disease and arthritis.