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Columbia University

Principal Investigators: Stavroula Kousteni and Gerard Karsenty

Stavroula Kousteni has studied transcriptional control of bone loss, relating the biology of ageing to the development of osteoporosis. The transcription factor FoxO1 has been identified as of interest for its role in bone remodelling. The lab also works with Gerard Karsenty’s group, in a systematic molecular study aiming at understanding the role of the skeleton in whole body physiology. Again, their work has indicated that osteoblast expressed FoxO1 can affect metabolic homeostasis by regulating pancreatic beta-cell proliferation, insulin secretion, and insulin sensitivity. Currently, the group 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, the group is examining the role of osteoblasts in cancer with a particular emphasis on Leukemia. Recent studies have shown that osteoblasts can regulate the number of hematopoietic stem cells (HSC) in several murine models. The lab has evidence that signals emanating from osteoblasts affect leukemia blast function. They are currently characterizing molecules involved and their mechanism of action.

Gerard Karsenty has pioneered research investigating bone as an endocrine organ with a link to energy metabolism. Testing this hypothesis allowed them to identify a bone-specific hormone called osteocalcin whose functions are to increase insulin secretion and sensitivity. Currently numerous studies in the lab are addressing at the molecular level the mechanism of action of osteocalcin in target cells as well as other aspects of its biology. Those include but are not limited to the identification of its receptor and of extracellular regulators of activity. The research focuses on mouse models and the group has strong expertise in the development of animal models including knockout mice.

The group have also shown recently that gut-derived serotonin is a hormone whose main function is to inhibit bone formation by osteoblast. Because they have elucidated the entire molecular cascade from the synthesis of the hormone to its target genes in osteoblasts, they are now in a position to test the therapeutic relevance of this pathway in the treatment of osteoporosis. This work on serotonin has triggered a more general interest in the lab about the possible role and mechanism of action of brain-derived serotonin in the control of bone mass. These projects focused on serotonin regulation of bone mass and address both basic physiological functions and its potential therapeutic outcome in humans.

The two Columbia labs are often hosting postdoctoral scientists from the laboratories of international collaborators. Additionally they have international collaborations with groups in Germany, France, Greece, and Japan. Dr Karsenty is internationally known in the field of bone research having held senior positions of responsibility in the American Society for Bone and Mineral Research and the International Bone and Mineral Society.

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. 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, 11:147-160, 2010.

3. Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G.Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.Cell. 2008 Nov 28;135(5):825-37.

4. Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010 Mar;16(3):308-12. Epub 2010 Feb 7.

5. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G. Endocrine regulation of male fertility by the skeleton. Cell. 2011 Mar 4;144(5):796-809. Epub 2011 Feb 17.

Click here to view latest publications of Stavroula Kousteni on PubMed

Click here to view latest publications of Gerard Karsenty on PubMed