Venezia by PVII

Dr. Gerard KarsentyGerard Karsenty, MD, PhD

Professor
Department of Molecular & Human Genetics
and Program in Developmental Biology
Baylor College of Medicine
karsenty@bcm.tmc.edu

MD/PhD, University of Paris V, France, 1984
Postdoc, National Institutes of Health, 1987
Postdoc, The University of Texas M.D. Anderson Cancer Center, 1990

The Biological Bases Controlling Bone Formation

Skeleton is an organ made of two tissues, bone and cartilage, and three cell types, chondrocytes in cartilage, osteoblast and osteoclast in bone. My laboratory is interested in two distinct aspects of skeleton biology; cell differentiation and all functions. We address both lines of research by focusing osteoblast a cell type of mesodermal origin that is responsible for bone formation.

Our work in trying to elucidate the molecular bases of osteoblast differentiation led us to identify Runx2 as a master gene of differentation. Runx2 is a transcription factor that is necessary and sufficient for osteoblast differentiation in both mice and humans. We have also shown that Runx2 function during osteoblast differentiation is dominant and haploinsufficiency at the Runx2 locus cause a classical human skeletal dysplasia called cleidocranial dysplasia (CCD). Pursuing this line of work we have used human genetic information to address two questions. First, how is Runx2 function regulated at a time during development where it is expressed but osteoblast differentiation does not occur. To address this question, we searched for human diseases having a phenotype opposite to the one of CCD and tested the genes causing these diseases as candidate genes. As it turned out, one of these genes, Twist-1, which is also a nuclear protein inhibits osteoblast differentiation by transiently inhibiting Runx2 function during development. Thus if Runx2 remains the master gene of osteoblast differentiation, Twist-1 acts as a gatekeeper in this process. Demonstration that it is the case was achieved in vivo and molecularly. The second question we asked was to identify additional transcription factors acting downstream of Runx2. To that end, we became interested in a human disease, Coffin Lowry Syndrome, caused by mutation in a kinase, RSK 2 , whose substrate has never been recognized. Using an array of molecular and genetic approaches, we identified ATF 4 as the substrate of RSK 2 in osteoblast and showed that ATF 4 is required for osteoblast differentiation downstream of Runx2. We also showed that ATF 4 is required for the maintenance of the osteoblast phenotype beyond development.

The second aspect of skeletal biology we are studying at the genetic level is skeleton physiology focusing on two functions: maintenance of bone mass and bone mineralization. We hypothesized that the control of bone mass occurred through brain relay. Testing this hypothesis led us to show that leptin is the most powerful hormone controlling bone mass and that leptin antiosteogenic function is a major function of this hormone. Leptin inhibits bone formation following its binding to its receptor on hypothalamic neurons. We have demonstrated that the sympathethic nervous system is the mediator of leptin antiosteogenic function not of its anorexigenic function. As expected drugs inhibiting the sympathetic nervous system prevent the appearance of osteoporosis in gonadectomized mice. The significance of these findings was greatly increased by the discovery that leptin regulates also bone resorption. Leptin regulation of bone resorption involves the sympathetic nervous system and another neupeptide called CART. Thus leptin is the only hormone regulating both aspects of bone remodeling. Lastly, to explore genetically the molecular bases of bones mineralization, we are studying the function of all genes affecting calcium and phosphate metabolism, as well as analyzing the pattern of expression of these genes and genes encoding proteins of the extracellular matrix to explain the spatial restriction of this process. This has allowed us to propose a model that is currently being tested.

Representative Publications:

Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature. 437(7057):417-421, 2005.

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

Xiao G, Jiang D, Ge C, Zhao Z, Lai Y, Boules H, Phimphilai M, Yang X, Karsenty G, Franceschi RT. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem. 280(35):30689-30696, 2005.

Kondo H, Nifuji A, Takeda S, Ezura Y, Rittling SR, Denhardt DT, Nakashima K, Karsenty G, Noda M. Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J Biol Chem. 280(34):30192-30200, 2005.

Karsenty G. An aggrecanase and osteoarthritis. N Engl J Med. 353(5):522-523, 2005.

Dabovic B, Levasseur R, Zambuto L, Chen Y, Karsenty G, Rifkin DB. Osteopetrosis-like phenotype in latent TGF-beta binding protein 3 deficient mice. Bone. 37(1):25-31, 2005.

Sakamoto A, Chen M, Nakamura T, Xie T, Karsenty G, Weinstein LS. Deficiency of the G-protein alpha-subunit G(s)alpha in osteoblasts leads to differential effects on trabecular and cortical bone. J Biol Chem. 280(22):21369-21375, 2005.

Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 8(5):751-764, 2005.

Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 19(9):1093-1104, 2005.

Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 434(7032):514-520, 2005.

Chien KR, Karsenty G. Longevity and lineages: toward the integrative biology of degenerative diseases in heart, muscle, and bone. Cell. 120(4):533-544. Erratum in: Cell. 121(1):153-4, 2005.

Giacopelli F, Marciano R, Pistorio A, Catarsi P, Canini S, Karsenty G, Ravazzolo R. Polymorphisms in the osteopontin promoter affect its transcriptional activity. Physiol Genomics. 20(1):87-96, 2004.

Chen YT, Levasseur R, Vaishnav S, Karsenty G, Bradley A. Bigenic Cre/loxP, puDeltatk conditional genetic ablation. Nucleic Acids Res. 32(20):e161, 2004.

Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, McAnally J, Pomajzl C, Shelton JM, Richardson JA, Karsenty G, Olson EN. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell. 119(4):555-566, 2004.

Yang X, Karsenty G. ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem. 279(45):47109-47114, 2004.

Cock TA, Back J, Elefteriou F, Karsenty G, Kastner P, Chan S, Auwerx J. Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen. EMBO Rep. 5(10):1007-1012, 2004.

Gordon CM, Bachrach LK, Carpenter TO, Karsenty G, Rauch F. Bone health in children and adolescents: a symposium at the annual meeting of the Pediatric Academic Societies/Lawson Wilkins Pediatric Endocrine Society, May 2003. Curr Probl Pediatr Adolesc Health Care. 34(6):226-242, 2004.

Wang W, Wang YG, Reginato AM, Glotzer DJ, Fukai N, Plotkina S, Karsenty G, Olsen BR. Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice. Dev Biol. 270(2):364-381, 2004.

Murshed M, Schinke T, McKee MD, Karsenty G. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol. 165(5):625-630, 2004.

Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 117(3):387-398, 2004.

Dacquin R, Mee PJ, Kawaguchi J, Olmsted-Davis EA, Gallagher JA, Nichols J, Lee K, Karsenty G, Smith A. Knock-in of nuclear localised beta-galactosidase reveals that the tyrosine phosphatase Ptprv is specifically expressed in cells of the bone collar. Dev Dyn. 229(4):826-834, 2004.

Elefteriou F, Karsenty G. [Bone mass regulation by leptin: a hypothalamic control of bone formation] Pathol Biol (Paris). 52(3):148-153, 2004.

Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A. 101(9):3258-3263, 2004.

Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G. A twist code determines the onset of osteoblast differentiation. Dev Cell. 6(3):423-435, 2004.

Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac JD, Karsenty G. Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol. 164(4):509-514.

Cui Y, Huang L, Elefteriou F, Yang G, Shelton JM, Giles JE, Oz OK, Pourbahrami T, Lu CY, Richardson JA, Karsenty G, Li C. Essential role of STAT3 in body weight and glucose homeostasis. Mol Cell Biol. 24(1):258-269, 2004.

Glass DA 2nd, Patel MS, Karsenty G. A new insight into the formation of osteolytic lesions in multiple myeloma. N Engl J Med. 349(26):2479-2480, 2003.

Elefteriou F, Takeda S, Liu X, Armstrong D, Karsenty G. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass. Endocrinology. 144(9):3842-3847, 2003.

Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T, Takayanagi H. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 17(16):1979-1991, 2003.

Terpstra L, Prud'homme J, Arabian A, Takeda S, Karsenty G, Dedhar S, St-Arnaud R. Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin linked kinase in chondrocytes. J Cell Biol. 162(1):139-148, 2003.

Fizazi K, Yang J, Peleg S, Sikes CR, Kreimann EL, Daliani D, Olive M, Raymond KA, Janus TJ, Logothetis CJ, Karsenty G, Navone NM. Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts. Clin Cancer Res. 9(7):2587-2597, 2003.

Levasseur R, Barrios R, Elefteriou F, Glass DA 2nd, Lieberman MW, Karsenty G. Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice. Endocrinology. 144(7):2761-2764, 2003.

Karsenty G. The complexities of skeletal biology. Nature. 423(6937):316-318, 2003.

Tu Q, Pi M, Karsenty G, Simpson L, Liu S, Quarles LD. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest. 111(7):1029-1037, 2003.

Cui CB, Cooper LF, Yang X, Karsenty G, Aukhil I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol. 23(3):1004-1113, 2003.

Takeda S, Elefteriou F, Karsenty G. Common endocrine control of body weight, reproduction, and bone mass. Annu Rev Nutr. 23:403-411, 2003.

Stheneur C, Dumontier MF, Guedes C, Fulchignoni-Lataud MC, Tahiri K, Karsenty G, Corvol MT. Basic fibroblast growth factor as a selective inducer of matrix Gla protein gene expression in proliferative chondrocytes. Biochem J. 369(Pt 1):63-70, 2003.

El-Maadawy S, Kaartinen MT, Schinke T, Murshed M, Karsenty G, McKee MD. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res. 44 Suppl 1:272-1278, 2003.

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