The osteoblast or bone forming cell s=is a cell of mesodermal origin that once fully differentiated produces the bone extracellular matrix and eventually mineralizes it. Alterations in osteoblast differentiation and/or function occur in several crippling genetic diseases and some degenerative diseases such as osteoporosis. The objective of this application is to use a combination of genetic, biochemical and molecular approaches centered around the osteocalcin gene, an osteoblast specific gene, to better understand the mechanisms governing osteoblast differentiation and function. Osteocalcin is a mineral binding protein of unknown function secreted y the osteoblast into the bone extracellular matrix at the time of bone mineralization. To understand osteocalcin function and thereby the function of the osteoblast during bone mineralization, we have generated an osteocalcin-deficient mouse through homologous recombination in embryonic stem cells. We plan to use this mouse model to study the functions of osteocalcin. We also intend to use these mutant mice to study osteocalcin interaction with other proteins secreted by osteoblasts in the bone extracellular matrix. To begin to decipher the mechanisms controlling osteoblast differentiation we will look for genes located upstream of the osteocalcin genes that control their osteoblast specific pattern of expression. For that purpose we will use a combination of transgenic mice analysis, DNA transfection experiments, DNA binding assays, and molecular cloning to identify, characterize, and eventually clone a cDNA coding for an osteoblast specific transcription factor. This dual study of the function and regulation of expression of a major biosynthetic product of the osteoblast should allow us to answer basic questions of cell biology centered around the function of the osteoblast in physiological and pathological circumstances.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011290-06
Application #
2897068
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Sharrock, William J
Project Start
1995-09-01
Project End
2000-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Karsenty, Gerard; Kronenberg, Henry M; Settembre, Carmine (2009) Genetic control of bone formation. Annu Rev Cell Dev Biol 25:629-48
Yang, Xiangli; Karsenty, Gerard (2004) ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem 279:47109-14
Yang, Xiangli; Karsenty, Gerard (2002) Transcription factors in bone: developmental and pathological aspects. Trends Mol Med 8:340-5
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Geoffroy, V; Corral, D A; Zhou, L et al. (1998) Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function. Mamm Genome 9:54-7

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