Faculty and Staff
Nutritional and Metabolic Doctoral Training Faculty
Stavroula Kousteni, Ph.D.
Assistant Professor of Medicine
Affiliation(s): Medicine, Institute of Human Nutrition
Research Interest(s): Molecular and cellular mechanisms controlling bone mass
The Russ Berrie Medical Sciences Pavilion
1150 St. Nicholas Avenue
New York, NY 10032
The adult skeleton is constantly renewed by the physiological process of bone remodeling, which includes two cellular events occurring in succession. The first one is resorption, or destruction of the mineralized bone matrix, by osteoclasts, and the second event is bone formation by osteoblasts. Osteoblasts and osteoclasts are bone-specific cell types derived from precursors originating in the bone marrow. The precursors of osteoblasts are multipotent mesenchymal stem cells which also give rise to bone marrow stromal cells, chondrocytes, myoblasts, and adipocytes. Due to their action as the bone forming cells, osteoblasts are an enticing target for treating bone loss. For this reason, our lab is interested in studying mechanisms that control their transcriptional activities.
Compromised osteoblast function is a main cause of osteoporosis, a low bone mass disease affecting virtually everyone as we age. To study the transcriptional control of bone loss in this context, we examined transcriptional mechanisms that could link the biology of aging with the pathogenesis of osteoporosis. One of the major deleterious events in aging is the generation of reactive oxygen species (ROS). Since the FoxO family of transcription factors, confers stress resistance, we investigated their potential impact on skeletal integrity. We have found through cell-specific gene deletion and molecular analyses that FoxO1 is required for proliferation and redox balance in osteoblasts, and as a result controls bone formation. FoxO1 regulation of osteoblast proliferation also occurs because of another function, its ability to regulate amino acid import. We are currently exploring molecular mechanisms by which FoxO1 interacts with other FoxO family members as well as other transcription factors, either specifically expressed in osteoblasts or more broadly expressed, to regulate bone remodeling.
Our lab has also embarked in a systematic molecular study aiming at understanding the role of the skeleton in whole body physiology. Since osteoblasts, the bone forming cells, influence glucose metabolism through secretion of a bone specific protein, we examined how this function is regulated transcriptionally. Again, and because FoxO1 is well known to regulate several key aspects of glucose homeostasis, we investigated whether its expression in osteoblasts may contribute to its metabolic functions. Our work indicated that osteoblast expressed FoxO1 can affect metabolic homeostasis by regulating pancreatic β-cell proliferation, insulin secretion, and insulin sensitivity. Mechanistically, these events stem from the ability of FoxO1 to regulate the activity and secretion of osteoblast-specific proteins. Hence, the notion emerging from our current work is that FoxO1 may be a general regulator of most functions of the osteoblast. Currently, we are exploring the role of other nuclear proteins alone, or by interaction with FoxO1, as modulators of the ability of the skeleton to function as an endocrine organ regulating glucose metabolism.
Within the context of studying signals originating from osteoblasts and influencing physiology or disease progression we are examining the role of osteoblasts in cancer with a particular emphasis on Leukemia. Survival rates for adults and mainly children with Acute Myeoloid or refractory lymphoid Leukemia remain low and, high dose chemotherapy has a limited impact in these diseases.. The interest of the lab is to determine whether there is communication between osteoblasts and leukemia blasts, and, whether this communication can be interrupted by drugs. Recent studies have shown that osteoblasts can regulate the number of hematopoietic stem cells (HSC) in several murine models. Our lab has evidence that signals emanating from osteoblasts affect leukemia blast function. We are currently characterizing molecules involved and their mechanism of action. We are also determining whether direct interaction between osteoblasts and leukemia blasts is needed to support leukemia engraftment in vivo in murine models. We expect that data from the experiments in this project may provide the rationale for using means to suppress the osteoblast and make the hematopoietic niche hostile to residual leukemia cells.
Recent Publications - Pubmed
Kousteni S., Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, and Manolagas SC. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell,104: 719-30, (2001).
Kousteni S., Chen J.-R., Bellido T. Han L., Ali A.A., O’Brien C.A., Plotkin L., Fu Q., Mancino A.T., Wen Y., Vertino A.M., Powers C.C., Stewart S.A., Ebert R., Parfitt A.M., Weinstein R.S., Jilka R.L. and Manolagas S.C. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science, 298:843-846, (2002).
Kousteni S., Han L., Chen J-R., Almeida M., Plotkin L.I., Bellido T. and Manolagas S.C. Kinase-mediated regulation of common transcription factors accounts for the bone protective effects of sex steroids. Journal of Clinical Investigation 111: 1651-1664, (2003).
Almeida M., Han L., Bellido T., Manolagas S. C. and Kousteni S. Wnts prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by β-catenin-dependent as well as independent signaling cascades involving Src/ERK and PI3K/Akt. Journal of Biological Chemistry, 280:41342-41351, (2005).
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, (2009).
Rached M.T., Kode A., Xu L., Paik J-H, DePinho R.A, Kousteni S. FoxO1 is a Positive Regulator of Bone Formation by Favoring Protein Synthesis and Resistance to Oxidative Stress in Osteoblasts. Cell Metabolism, Published Online February 3, (2010).