Transgenic approaches to evaluate IGF-I role in peak BMD

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DESCRIPTION (provided by applicant): Osteoporosis is a disease characterized by low peak bone mass leading to higher fragility where fractures occur after minimal trauma. Therefore, of considerable importance in the prevention and treatment of osteoporosis are those studies that focus on understanding the mechanisms regulating bone accretion during critical windows in time when rapid bone accretion takes place. To this end, our studies involving conditional knockout of IGF-I by Cre/LoxP approach during the past grant period have provided unequivocal experimental evidence that IGF-I produced locally in bone plays a key role in the acquisition of peak bone mass during prepubertal growth period. Our studies also have lead to an unexpected important conclusion that a great deal of the IGF-I action during the prepubertal growth period is regulated by a growth hormone (GH)-independent mechanism. In this continuation grant, we have proposed a novel hypothesis that the rapid increase in IGF-I expression during prepubertal growth period is regulated by thyroid hormone (TH), independent of GH. To test the hypothesis that IGF-I expression during prepubertal growth period is regulated predominantly by TH, we will use TSH receptor and dual oxidase 2 mutant mouse models which are deficient in TH and test the cause and effect relationship between an increase in TH production and IGF-I expression during the prepubertal growth period. To establish that TH regulates IGF-I expression independent of GH, we will use GH-deficient lit/lit mouse model with a mutation in GH-releasing hormone receptor. To test the hypothesis that the TH effect on IGF-I expression during the prepubertal growth period is mediated via TH receptor (TR)a1, we will examine if TRa1 and IGF-I are coexpressed in specific cell types in bone. We will disrupt TRa1 function in osteoblasts by conditional knockout approach and evaluate the consequence of TRa1 disruption on IGF-I expression and skeletal phenotype during prepubertal growth period. To test the hypothesis that TH effects on bone are mediated via increased bone cell production of IGF-I, we will delete IGF-I from floxed osteoblasts using adenoviral Cre and test TH effects on osteoblast proliferation and differentiation in vitro. To test the role of locally produced IGF-I on bone formation in vivo, we will test the effects of TH on skeletal changes in conditional IGF-I knockout out mice in which IGF-I gene is disrupted in osteoblasts and corresponding control mice. Because IGF-I is a very important growth factor and because little is known about the regulation of IGF-I expression during prepubertal growth period, the confirmation of our hypothesis that TH is a major regulator of IGF-I expression during prepubertal growth period and that TH effects on bone are mediated via local production of IGF-I, could lead to the development of effective therapies, based on TH action, to treat children with growth disorders during a window in time when rapid growth occurs. PUBLIC HEALTH RELEVANCE: The amount of bone formed early in childhood is a very important determining factor in terms of whether or not the individual will develop osteoporosis later in life. Therefore, it is great importance to understand the molecular mechanisms that contribute to skeletal changes that occur during the early growth period. This study will test a novel hypothesis that Insulin-like growth factor (IGF)-I effects on skeletal growth is predominantly mediated via thyroid hormone via a mechanism that is independent of growth hormone. Because IGF-I is proven to be an extremely important molecule in the regulation of bone formation process, the confirmation of the hypothesis that IGF-I produced locally in bone in response to thyroid hormone plays a major role in the rapid increase in bone accretion that takes place during the unique window in time during the prepubertal growth period will have future ramifications concerning strategies to increase peak bone mass.