The long-term goal of AR45433 had been to define the genetic determinants of IGF-I using two inbred strains of mice, B6 and C3H. We were successful in identifying the strongest QTL for IGF-I and bone density on mouse Chr6, and made a congenic mouse (6T) that carried this locus from C3H, on a B6 background. 6T mice had low bone mass, reduced IGF-I, and enhanced marrow adiposity, but increased insulin sensitivity. Using in silico data bases, expression profiling and sequencing, we excluded one candidate gene, and ascertained that Pparg polymorphisms were a major contributor to the 6T metabolic and skeletal phenotypes. In 6T mice we noted marked up regulation of a Ppar3 -inducible gene, Nocturnin (Noc), which is a circadian deadenylase that targets long 3'UTRs and causes destabilization of mRNA transcripts. In contrast we found that Noc null mice had high bone mass and reduced marrow fat. In vitro silencing of the Noc gene in adipocytes caused an increase in Igf1 transcripts and a reduction in downstream adipogenic markers. Hence, in this proposal we postulate that Pparg regulates IGF-I through activation of Noc, leading to enhanced adipogenesis but destabilization of Igf1mRNA and impaired MSC allocation into bone. To test that hypothesis, we propose 2 specific aims:
Specific Aim 1 : Determine the role of Noc in skeletal acquisition and maintenance. We will comprehensively define the skeletal and metabolic phenotypes of three mouse strains on a regular and high fat diet and after rosiglitazone treatment: a- Noc null mice, b-:conditional adipose specific Pparg deleted (FKO 3) mice.,and c- B6 littermate controls.
Specific Aim 2 : Interrogate the molecular mechanisms that define Noc actions on IGF-I and MSC allocation. We will determine Igf1 mRNA stability in B6, 6T and Noc-/- mice,and examine the deadenylating activity of NOC in B6 and 6T. We will also assess the time course of Noc expression in adipocytes and MSCs, and determine how silencing of Noc affects Igf1 and downstream adipogenic and osteogenic targets. Delineating the effects of Noc on skeletal acquisition and maintenance will provide a clearer perspective about age-relate bone loss, and the fate of marrow stromal cells relative to bone and fat. Moreover, identification of a non-transcriptional pathway that regulates IGF-I would have major implications for epidemiologic studies of circulating IGF-I and its relationship to longevity, cancer risk, and osteoporosis. It could also reveal new targets for therapeutic intervention to blunt or enhance IGF-I actions in tissue specific sites.
Our studies will provide valuable insight into the significance of one gene, Nocturnin, that is important in the origin of both fat and bone cells. The exploration of its nature as a light-dark cycle gene regulating the production of insulin-like growth factor 1 should clarify the importance of this pathway in normal bone maintenance, as well as age- related osteoporosis.
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