Stavroula Kousteni, Ph.D.
Professor of Physiology and Cellular Biophysics
Skeletal functions in metabolism and hematopoiesis.
The purpose of the research in my laboratory is to understand the influence of the skeleton on various physiological processes. The long term goal is to uncover the pathogenesis of degenerative diseases and to suggest novel and adapted therapies for them. Along these lines we are studying the function of bone as an endocrine organ regulating glucose metabolism and energy homeostasis and examining the role of osteoblasts in hematopoiesis with particular emphasis in myelodysplasia (MDS) and acute myeloid leukemia (AML).
Bone as an endocrine organ
Osteoblasts, the bone forming cells, have been shown previously to influence glucose metabolism through the secretion of a bone-specific hormone, osteocalcin. We found that the activity of osteocalcin is regulated transcriptionally by osteoblast-expressed FoxO1. These findings raised for us the question of the nature of the osteoblast as an endocrine cell, and more specifically whether it secretes other hormones regulating any aspect of energy metabolism. Using a genetic approach to this problem we identified a second osteoblast-specific hormone that affects glucose metabolism and insulin secretion. We are currently expanding this work, searching for its receptor and for other functions and mechanisms of action exerted by this hormone.
Detecting Interactions between Osteoblasts and Leukemia Blasts
In current work, our lab has discovered a function of the skeleton, as an inducer of leukemogenesis. We identified a mutation in the osteoblast that disrupts hematopoiesis leading to leukemogenic transformation of hematopoietic stem cells (HSCs) and establishment of MDS progressing to AML. The same mutation and signaling pathway were identified in more than a third of patients with MDS and AML. We have also found that osteoblasts affect engraftment of leukemia blasts. We are currently characterizing the signaling pathway that mediates these actions. This work may provide a rationale for using means to manipulate the osteoblast to make the hematopoietic niche hostile to residual leukemia cells.
Galan-Diez M, Borot F, Mahmood Ali A, Zhao J, Gil-Iurbe E, Shan X, Luo N, Liu Y, Huang X-P, Bisikirska B, Labella R, Kurland I, Roth BL, Quick M, Mukherjee S, Raul Rabadan, Carroll M, Raza A and Kousteni S. (2022) Subversion of serotonin-receptor signaling in osteoblasts by kynurenine drives Acute Myeloid Leukemia. Cancer Discovery DOI: 10.1158/2159-8290.CD-21-0692
Petropoulou P.I., Mosialou I., Shikhel S., Hao L., Panitsas K., Bisikirska B., Luo N., Bahna F., Kim J., Carberry P., Zanderigo F., Simpson N., Bakalian M., Kassir S., Shapiro L., Underwood M.D., May C.M, Sai K.K.S., Jorgensen M.J., Confavreux C.B., Shapses S., Laferrère B., Mintz A., Mann J.J., Rubin M. and Kousteni S. Lipocalin-2 is an anorexigenic signal in primates eLIfe, 2020;9:e58949 doi: 10.7554/eLife.58949.
Mosialou I., Shikhel S., Luo N., Petropoulou P.I., Panitsas K., Bisikirska B., Rothman N.J., Tenta R., Cariou B., Wargny M., Sornay-Rendu E., Nickolas T., Rubin M., Confavreux C. B., Kousteni S. Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes. Journal of Experimental Medicine (2020) 217 (10): e20191261.
Tikhonova A.N., Dolgalev I., Hu H., Sivaraj K.K., Hoxha E., Cuesta-Domínguez A., Pinho S., Akhmetzyanova I., Gao J., Witkowski M., Guillamot M.R, Gutkin M.C., Zhang Y., Marier C., Diefenbach C., Kousteni S., Heguy A., Fooksman D.R., Butler J.M., Economides A., Frenette P.S., Adams R.H., Satija R., Tsirigos A., and Aifantis I. “Transcriptomic profiling of the bone marrow microenvironment at single cell resolution”. Nature, 569:222-228, 2019.
Cohen A, Kousteni S, Bisikirska B, Shah JG, Manavalan JS, Recker RR, Lappe J, Dempster DW, Zhou H, McMahon DJ, Bucovsky M, Kamanda-Kosseh M, Stubby J, Shane E. IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis. Journal of Bone and Mineral Research, 32:1267-1273, 2017.