Crtap function during skeletal homeostasis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Osteoporosis is a common bone disease characterized by low bone mass and deterioration in the microarchitecture, with a consequent increase in bone fragility and susceptibility to fractures. Primary osteoporosis can be due to attainment of lower peak bone mass during puberty and early adulthood, and/or to an unbalance between bone formation and bone resorption. Genetic factors are a primary determinant of this and animal models have been extremely helpful for identifying new genes and pathways that play a role in this process. This proposal focuses on a novel gene that could be important in a crucial pathway that regulates bone formation, the synthesis of fibrillar collagens. In an effort to identify new gene in the regulation of cartilage and bone formation, we previously identified a gene by differential screening of in vitro cultured chondrocytes and named it Crtap (Cartilage Associated Protein). To understand its in vivo function, we generated a null mutant mouse for the Crtap gene. Our initial observations show that the Crtap null mice develop a severe early onset osteoporosis and age-related kyphosis. To comprehend the functional characteristics of the Crtap gene we propose to systematically analyze the consequences of Crtap loss of function during skeletal formation and homeostasis. First, histological, histomorphometric, micro-CT and biochemical analyses will be performed to better characterize the skeletal phenotype of the Crtap-/- mice and hence determine whether the bone defect is secondary to dysregulated bone formation and/or bone resorption. Second, we will perform functional in vitro studies on primary cultures of osteoblasts and osteoclasts in order to identify cell-autonomous defects. These initial experiments are expected to begin elucidating the function of the Crtap gene during bone formation and homeostasis and its role in the pathogenesis of osteoporosis. Importantly, they may identify a new regulator of collagen post-translational modification, folding, assembly or secretion.