The purpose of the research in my laboratory is to understand the influence of the skeleton on various physiological processes and in disease. 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 examining the role of osteoblasts in hematopoiesis with particular emphasis in myelodysplasia (MDS) and acute myeloid leukemia (AML) and studying the function of bone as an endocrine organ regulating glucose metabolism and energy homeostasis.
Detecting Interactions between Osteoblasts and Leukemia Blasts
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.
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, Lipocalin 2, that suppresses appetite and at the same time promotes energy expenditure, beta cell proliferation and insulin secretion.
1. Rached M.T., Kode A., Silva B.C., Jung D-Y, Gray S., Ong H., Paik J-H, DePinho R.A., Kim J.K., Karsenty G., Kousteni S. The Osteoblast, a Novel Site of Action for FoxO1 Regulation of Glucose Homeostasis. Journal of Clinical Investigation, 149:5713-5723, 2010
2. Kode A., Silva B.C., Ferron M., Rached M.T. and Kousteni S. FoxO1 cooperates with ATF4 in osteoblasts to control glucose homeostasis. Journal of Biological Chemistry 287:8757-8768, 2012
3. Kode A., Mosialou I., Silva B.C., Rached M-T, Zhou B., Wang J., Townes T.M, Hen R, DePinho R.A., Guo X.E, Kousteni S. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. Journal of Clinical Investigation 122: 3490-3503, 2012
4. Kode A., Manavalan S.J, Mosialou I., Bhagat G., Rathinam C.V, Luo N., Khiabanian F., Lee A., Vundavalli M., Friedman R., Brum A., Park D., Galili N., Mukherjee S., Teruya-Feldstein J., Raza A., Rabadan R., Berman E. andKousteni S. Leukemogenesis Induced by an Activating b-catenin mutation in Osteoblasts. Nature, 506:240-244, 2014.
5. Krevvata M., Silva B.C., Manavalan J.S., Galan-Diez M., Kode A., Matthews G.B., Park D., Zhang C.A. Galili N., Nickolas T.L., Dempster D.W., Dougall W., Teruya-Feldstein J., Economides A.N. Kalajzic I., Raza A., Berman E., Mukherjee S., Bhagat G., and Kousteni S. Inhibition of Leukemia Cell Engraftment and Disease Progression in Mice by Osteoblasts. Blood, 124: 2834-2846, 2014.
6. Kode A., Mosialou I., Manavalan J.S., Friedman R.A., Teruya-Feldstein J., Bhagat G., Berman E. and Kousteni S. FoxO1-Dependent Induction of Acute Myeloid Leukemia by Osteoblasts in Mice. Leukemia, 30:1-13, 2016.
7. Mosialou I., Shikhel S., Liu J.-M., Maurizi A., Luo N., He Z.,, Huang Y.,, Zong H., Friedman R.A., Barasch J., Lanzano P., Deng L., Leibel R.L., Rubin M., Nicholas T., Chung W., Zeltser L.M., Williams K.W., Pessin J.E. andKousteni S. MC4R-Dependent Suppression of Appetite by Bone-Derived Lipocalin 2. Nature, 543:385-390, 2017.