Gerard Karsenty, M.D. Ph.D.

Research Summary

A Molecular Genetic Analysis of Skeletal Biology

As it is the case for every organ two distinct questions face biologists studying skeleton. Those are how does it develop, and how does it execute its functions? In the first 10 years of its existence our laboratory focused its effort on the developmental aspect of skeletal biology and tried to elucidate the transcriptional network controlling bone formation. This resulted in the identification of positive and negative regulations of osteoblast differentiation. In particular, the lab identified Runx2 as the master gene of osteoblast differentiation and ATF4 as the main regulator of osteoblast functions.

Without abandoning totally this line of research the lab is now focusing mainly on skeleton physiology. More precisely we are asking three related questions: what are all the functions of the skeleton? What is the genetic cascade accounting for these functions? And lastly, can we use this knowledge to understand the molecular bases of various diseases and to propose adopted therapies? The work in this area started on bone remodeling, the process whereby bone mass is maintained constant throughout adulthood. Because of some clinical information we hypothesized that bone mass, body weight and reproduction must be regulated by the same hormones. Testing this hypothesis in vivo led us to show that the adipocyte-derived hormone leptin does regulate appetite, reproduction and bone mass. We further showed that this requires the involvement of hypothalamic neurons that affect bone mass through two neuron mediators, the sympathetic tone and CART (cocaine amphetamine regulated transcript). This work provided more improved understanding of the pathophysiology of osteoporosis, the main disease of bone remodeling, and suggested a rationale treatment for this disease. We are now looking at various unanswered molecular aspects of this novel regulation of bone mass.

The regulation of bone mass by leptin an adipocyte-derived hormone begged the following question, are osteoblasts exerting a feed-back regulation of adipocytes? In other words is bone and endocrine organ regulating energy metabolism? While testing this hypothesis we have identified two genes regulating not only adipocyte biology but also pancreas biology we have also shown that these tow genes are located in the same pathway. This novel line of research is rapidly expanding in the laboratory as it not only verifies the concept of a common endocrine regulation of bone mass and body weight but it also provides additional clues to the pathogenesis of the most frequent degenerative diseases in developed countries, the metabolic syndrome.

1. Hinoi E, Bialek P, Chen Y, Rached M, Groner Y, Behringer R, Ornitz D and Karsenty G. (2006). Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes & Development. In Press.

2. Dobreva G, Chahrour M, Dautzenberg M, Chirivella L, Kanzler B, Farinas L, Karsenty G, Grosschedl R. (2006). SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell, 125(5): 840-842.

3. Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G. (2005). The molecular clock mediates leptin-regulated bone formation. Cell, 122(5): 803-815.

4. Elefteriou F, Ahn JD,Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C and Karsenty G. (2005). Leptin regulation of bone resorption via the sympathetic nervous system and CART. Nature, 434: 514-520.

5. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka H, Schinke T, Li L, Townes T, Hanauer A, Karsenty G. (2004). ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry Syndrome. Cell, 117: 3870-398.

6. Bialek P, Kern B, Yank X, Schrock M, Sosic D, Hong N, Wu H Yu K, Ornitz D, Olson E, Justice M, Karsenty G. (2004). A Twist code determines the onset of osteoblast differentiation. Developmental Cell, 6:423-435.

7. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao, L, Parker DL, Armstrong D, Ducy P, Karsenty G. (2002). Leptin regulates bone formation via the sympathetic nervous system. Cell, 111(3): 305-317.