Control of Skeletal Growth by ATF-2

描述（由申请人提供）：控制生长板软骨细胞的进展对正常的骨和骨髓形成至关重要。PTHrP受体、FGFR3受体、TGF β受体II型、维生素D受体和甲状腺激素受体等基因的破坏可导致小鼠生长板的紊乱和软骨内成骨异常。多种人类遗传和获得性骨骼疾病是由于生长板中软骨细胞增殖和成熟之间的平衡受到干扰而导致的，包括软骨发育不良、过度生长疾病，如Beckwith Wiedernann综合征、骨软骨瘤和其他软骨肿瘤，以及某些形式的骨关节炎。激活转录因子2 （activated transcription factor 2, ATF-2）靶向许多不同基因中的环AMP应答元件（cyclic AMP response element， CRE），导致基因转录的激活。小鼠中ATF-2基因的突变导致生长板软骨细胞中ATF-2缺失和软骨内成骨缺陷，类似于人软骨发育不良，这是一种由于FGFR3受体激活突变而导致的侏儒症。atf -2缺陷小鼠的存活率大大降低，并表现出生长板表型，包括增殖区和肥厚区都减少。本提案的总体目标是确定ATF-2在控制软骨细胞增殖和生长板进展中的作用。该提案主要针对ATF-2的8个基因靶点：细胞周期蛋白D1、细胞周期蛋白A、c-Fos、c-Jun、视网膜母细胞瘤蛋白（pRb）、p107、p130和Bcl-2。除Bcl-2外，其余均直接参与细胞周期进程，因此是软骨细胞增殖的调节因子。Bcl-2在细胞凋亡的调控中起作用，细胞凋亡发生在生长板肥大带的末端软骨细胞中。本研究利用ATF-2缺陷小鼠生长板进行分子分析：1)ATF-2对靶基因的直接和间接影响；2)缺乏ATF-2时靶基因表达减少的后果；3)导致正常I或异常生长板软骨细胞增殖和进展的信号通路的定义。

DESCRIPTION (provided by applicant): 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.