Nocturnin suppresses igf1 expression in bone by targeting the 3' untranslated region of igf1 mRNA

IGF-I is an anabolic factor that mediates GH and PTH actions in bone. Expression of skeletal Igf1 differs for inbred strains of mice, and Igf expression levels correlate directly with bone mass. Previously we reported that peroxisome proliferator-activated receptor-γ2 activation in bone marrow suppressed Igf1 expression and that peroxisome proliferator-activated receptor-γ2 activation-induced Nocturnin (Noc) expression, a circadian gene with peak expression at light offset, which functions as a deadenylase. In 24-h studies we found that Igf1 mRNA exhibited a circadian rhythm in femur with the lowest Igf1 transcript levels at night when Noc transcripts were highest. Immunoprecipitation/RT-PCR analysis revealed a physical interaction between Noc protein and Igf1 transcripts. To clarify which portions of the Igf1 3' untranslated region (UTR) were necessary for regulation by Noc, we generated luciferase constructs containing various lengths of the Igf1 3'UTR. Noc did not affect the 170-bp short-form 3'UTR, but suppressed luciferase activity in constructs bearing the longer-form 3'UTR, which contains a number of potential regulatory motifs involved in mRNA degradation. C57BL/6J mice have low skeletal Igf1 mRNA compared with C3H/HeJ mice, and the Igf1 3' UTR is polymorphic between these strains. Interestingly, the activity of luciferase constructs bearing the long-form 3'UTR from C57BL/6J mice were repressed by Noc overexpression, whereas those bearing the corresponding region from C3H/HeJ were not. In summary, Noc interacts with Igf1 in a strain- and tissue-specific manner and reduces Igf1 expression by targeting the longer form of the Igf1 3'UTR. Posttranscriptional regulation of Igf1 may be critically important during skeletal acquisition and maintenance.