Kim C. Mansky, Ph.D. Assistant Professor School of Dentistry University of Wisconsin, Madison, 1997, Ph.D. kmansky@umn.edu 612-626-5582 office 612-624-0986 lab

Research Interests:

RANKL signaling and MITF activation of genes.

Bone is often thought to be a tissue that does not change once it is formed. However, bone is very dynamic and is constantly being remodeled. In healthy individuals, bone formation and resorption are in balance. Osteoporosis, which affects ten million people in the United States and puts at risk another thirty-four million Americans, is a result of the uncoupling of bone formation and resorption. Other diseases such as breast and prostate cancer or multiple myeloma cause changes in bone density indirectly through the action of tumor cells. Women with advanced breast cancer almost always develop bone metastases. Bone metastases are usually associated with bone pain and an increase in the susceptibility to fractures thought to be a result of the breakdown of bone caused by the presence of tumor cells. Other diseases such as rheumatoid arthritis can also result in bone loss.

There are two types of bone cells that are involved in bone remodeling: 1) cells that form bone (i.e., osteoblasts) and 2) cells that resorb bone (i.e., osteoclasts). The receptor activator of NF-KB ligand (RANKL) signaling pathway leads to osteoclast differentiation from cells of the monocyte/macrophage lineage. Our research interests lie in understanding the mechanism by which the RANKL signaling pathway leads to the persistent phosphorylation of p38 mitogen-activated protein kinase (MAPK) in osteoclasts. One long term goal of our research is to identify the signaling components of the RANKL pathway necessary for activating p38 MAPK in osteoclasts using both stable cell lines and RNA interference. We are also currently using 2D gel electrophoresis and mass spec to identify proteins expressed specifically in osteoclasts that are phosphorylated by p38 MAPK. We have already identified one substrate of the p38 MAPK in osteoclasts, the Microphthalmia-associated transcription factor (MITF). MITF is a transcription factor that is present in several different cell types as well as in osteoclasts. We have shown that MITF activates target genes that are necessary for osteoclast differentiation and activation. Knowledge of the cell signaling pathways involved in osteoclast differentiation and bone remodeling should allow for the development of innovative approaches to bone-associated disease prevention..

Selected Recent Publications:

• Bronisz A, Sharma SM, Hu R, Godlewski J, Tzivion G, Mansky KC, Ostrowski
  MC. 2006. Microphthalmia-associated transcription factor interactions with
  14-3-3 modulate differentiation of committed myeloid precursors. Mol Biol
  Cell. 17:3897-906.

• Wei G, Schaffner AE, Baker KM, Mansky KC, Ostrowski MC. 2003. Ets-2
  interacts with co-repressor BS69 to repress target gene expression. Anticancer Research 23:2173-8.

• Mansky, K.C., Sankar, U., Han, J., and Ostrowski, M.C. 2002. Microphthalmia transcription factor (MITF) is a target of p38 MAP kinase pathway in response to RANK ligand signaling. JBC 277:11077-11083.

• Mansky, K.C., Sulzbacher, S., Purdom, G., Nelsen, L., Hume,D.A., Rehli, M. and Ostrowski, M.C. 2002. The microphthalmia transcription factor and the related helix-loop-helix factors TFE-3 and TFE-C collaborate to activate the tartrate-resistant acid phosphatase promoter. Journal of Leukocyte Biology 71: 304-310.
  

• Mansky, K.C., Marfatia, K., Purdom, G., Luchin, A., Hume, D.A., and Ostrowski, M.C.2002. The microphthalmia transcription factor (MITF) contains two N-terminal domains required for transactivation of osteoclast target promoters and rescue of mi mutant osteoclasts. Journal of Leukocyte Biology 71; 295-303.

Last modified on: February 2, 2007