Kim C. Mansky, Ph.D.
School of Dentistry
University of Wisconsin, Madison, 1997, Ph.D.
Bone biology and bone cancer; Osteoimmunology; Bone metabolic disorders associated with HIV infection and antiretroviral therapy
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. Our lab has general interests in the cell signaling between the two types of bone cells that are involved in bone remodeling – osteoblasts (i.e., cells that form bone) and osteoclasts (i.e., cells that resorb bone) – and how perturbation of this signaling can lead to bone or bone-associated disease.
Osteoimmunology studies the interface and crosstalk between the skeletal and immune systems. In particular, osteoimmunology studies the shared components and mechanisms between the two systems, which include the ligands, receptors, signaling molecules and transcription factors. The bone marrow is important for the proper development of the immune system, and has important stem cells that maintain the immune system. Cytokines produced by immune cells (e.g., RANKL, M-CSF, TNFa, interleukins and interferons) can also have important effects on regulating bone homeostasis. The balance between bone modeling and remodeling can be perturbed during chronic inflammation, which can lead to bone metabolic disorders as well as bone pain. We have a particular interest in osteoimmunology as it relates to rheumatoid arthritis, HIV infection, and periodontal disease.
Metabolic disorders associated with highly active antiretroviral therapy (HAART) regimens are becoming increasingly important in the chronically HIV-infected population that has access to therapy. Clinical observations have revealed a strong correlation of bone density loss in HIV-infected individuals during HAART, particularly in conjunction with the antiretroviral drug tenofovir – a nucleotide analog that inhibits HIV reverse transcriptase. We are interested in understanding how tenofovir affects bone mineral density and to apply this knowledge for the identification of biomarkers and for developing adjuvant therapies to reduce bone mineral density loss during HAART.
Selected Recent Publications:
- Broege A, Pham L, Jensen ED, Emery A, Huang TH, Stemig M, Beppu H, Petryk A, O'Connor M, Mansky K, Gopalakrishnan R. 2013. Bone morphogenetic proteins signal via SMAD and MAP kinase pathways at distinct times during osteoclastogenesis. Journal of Biological Chemistry. Epub ahead of print.
- Mansky KC, Jensen ED, Davidova J, Yamamoto M, Gopalakrishnan R. 2013. Protein kinase d promotes in vitro osteoclast differentiation and fusion. J Biol Chem. 288:9826-34.
- Pham, L., Kaiser, B., Romsa, A., Schwarz, T., Gopalakrishnan, R., Jensen,
E.D., and Mansky, K.C. 2011. HDAC3 and HDAC7 have opposite effects on
osteoclast differentiation. Journal of Biological Chemistry, 286:112056-65.
- Pham, L., Beyer, K., Jensen, E., Rodriguez, J.S., Davydova, J., Yamamoto, M., Petryk, A., Gopalakrishnan, R., and Mansky, K.C. 2011. Bone morphogenetic protein 2 signalling in osteoclasts in negatively regulated by the BMP antagonist, twisted gastrulation. Journal of Cellular Biochemistry, 112(3):793-803.
- Mansky, K.C. 2010. Aging, human immunodeficiency virus, and bone health. 2010. Clinical Interventions in Aging, 5:285-292.
- Schwarz, T., Murphy, S., Sohn, C., and Mansky, K.C. 2010. C-TAK1 interacts with micropthalmia-associated transcription factor, Mitf, but not the related family member Tfe3. Biochemical and Biophysical Research Communications, 394:890-895.
- Grigsby, I.F., Pham, L., Mansky, L.M., Gopalakrishnan, R., Carlson, A. and Mansky, K.C. 2010. Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. Biochemical and Biophysical Research Communications, 394:48-53.
- Schwarz, T., Sohn, C., Kaiser, B., Murphy, S., Jensen, E.D., Gopalakrishnan, R. and Mansky, K.C. 2010. The 19S proteosomal lid subunit POH1 enhances the transcriptional activity of Mitf in osteoclasts. Journal of Cellular Biochemistry, 109:967-974.
- Jensen, E.D., Pham, L., Billington, C.J., Espe, K., Carlson, A.E., Westendorf, J.J., Petryk A., Gopalakrishnan, R., and Mansky, K.C. 2010. Bone Morphogenetic Protein 2 Directly Enhances Differentiation of Murine Osteoclast Precursors. Journal of Cellular Biochemistry 109:672-682.
- Grigsby,I.F., Pham, L., Gopalakrishnan, R., Mansky, L.M., and Mansky, K.C. 2010. Downregulation of Gnas, Got2 and Snord32a following tenofovir exposure of primary osteoclasts. Biochemical and Biophysical Research Communications 391:1324-1329.
- Grigsby, I.F., Pham, Lan, Mansky, L.M, Gopalakrishnan, R., and Mansky, K.C. 2009. Tenofovir-associated bone density loss. Therapeutics and Clinical Risk Management. 6:41-47.
- Rodriguez, J.S., Mansky, K.C., Jensen, E.D., Carlson, A., Schwarz, T., Pham, L., MacKenzie, B., Prasad, H., Rohrer, M.D., Petryk, A. and Gopalakrishan, R. 2009. Enhanced osteoclastogenesis causes osteopenia in Twisted gastrulation-deficient mice. Journal of Bone and Mineral Research 24:1917-26.
- Suttamanatwong, S., Jensen, E.D., Schilling, J., Franceschi, R.T., Carlson, A.E., Mansky, K.C. and Gopalakrishnan, R. 2009. Sp proteins and Runx2 mediate regulation of matrix gla protein (MGP) expression by parathyroid hormone. Journal of Cellular Biochemistry 15:284-92.
- Sharma, S.M., Bronisz A., Hu, R., Patel K., Mansky, K.C., Sif, S., and Ostrowski, M.C. 2007. MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. Journal of Biological Chemistry 282:15921-15929.
- 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
- 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.