Control of growth plate chondrocyte progression is essential for proper bone and marrow formation. Disruptions in several genes such as those for the PTHrP receptor, FGFR3 receptor, TGF beta receptor type II, vitamin D receptor, and thyroid hormone receptor result in disorganization of the growth plate and abnormal endochondral ossification in mice. Multiple human genetic and acquired skeletal disorders result from the perturbation of the balance between chondrocyte proliferation and maturation in the growth plate, including chondrodysplasias, overgrowth diseases like Beckwith Wiedernann syndrome, osteochondromas and other cartilage neoplasms, and some forms of osteoarthritis. Activating transcription factor 2 (ATF-2) targets the cyclic AMP response element (CRE) in many different genes and results in the activation of gene transcription. A mutation in the ATF-2 gene in mice results in the absence fo ATF-2 in growth plate chondrocytes and defects in endochondral ossification resembling human hypochondroplasia, a dwarfism due to activating mutations in the FGFR3 receptor. ATF-2-deficient mice have a substantially reduced survival rate, and display a growth plate phenotype that encompasses reductions in both the proliferative and hypertrophic zones. The overall goal of this proposal is to define the roles of ATF-2 in control of chondrocyte proliferation and growth plate progression. The proposal is focused on eight gene targets of ATF-2: those for cyclin D1, cyclin A, c-Fos, c-Jun, the retinoblastoma protein (pRb), p107, p130,and Bcl-2. All but Bcl-2 are directly involved in cell cycle progression, and therefore are regulators of chondrocyte proliferation. Bcl-2 plays a role in the control of apoptosis, which occurs in the terminal chondrocytes of the hypertrophic zone in the growth plate. This proposal exploits the growth plates of ATF-2-deficient mice for molecular analyses of 1) the direct and indirect effects of ATF-2 on target genes; 2) the consequences of reductions in expression of the target genes in the absence of ATF-2; and 3) the definition of signaling pathways that result in normal I or abberant growth plate chondrocyte proliferation and progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049355-05
Application #
7393638
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2004-04-15
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$273,554
Indirect Cost
Name
University of Florida
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Vale-Cruz, Dustin S; Ma, Qin; Syme, Janet et al. (2008) Activating transcription factor-2 affects skeletal growth by modulating pRb gene expression. Mech Dev 125:843-56
Ma, Qin; Li, Xinying; Vale-Cruz, Dustin et al. (2007) Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes. J Cell Biochem 101:477-87