To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cremediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required.Body size and linear bone growth in mammals is affected by cellular signaling pathways controlled by growth factors and hormones (1). In this regard, a major growth-promoting signaling system consisting of the insulin-like growth factors (IGF, 1 IGF1 and IGF2) and the type 1 IGF receptor (IGF1R) regulates embryonic growth, as shown by gene knockout experiments in mice (1). IGF1 acting through IGF1R also plays central roles in postnatal growth either independently or by mediating growth hormone functions (2). Signaling through the IGF1R tyrosine kinase receptor not only promotes cell proliferation, but also mediates anti-apoptotic actions (3, 4). The IGF system includes a second receptor (IGF2R) devoid of signaling properties, but serving IGF2 turnover, and at least six IGF-binding proteins (IGFBPs) of obscure functional significance (single and also some double mouse mutations ablating IGFBPs have not revealed as yet significant consequences in growth impairment). 2 The IGFs are produced locally in various tissues, including bones, and exert autocrine/paracrine functions, but they are also present in serum, mostly associated with IGFBPs. Whether the circulating IGFs act systemically as hormones is currently controversial (5, 6).A number of in vitro and in vivo studies are progressively unraveling the significance of the IGF system for skeletal development and metabolic control (for a review see Ref. 7). IGF1, by stimulating the proliferation of chondrocytes in the growth plate, plays an essential role in longitudinal bone growth (2) and is also involved in the formation of trabecular bone. In fact, chondrocytes and bone cells produce IGFs and express IGF1R (see for example Refs. 8 and 9). Studies using osteoblast culture systems have shown that IGF1 stimulates osteoblast proliferation, accelerates their differentiation, and enhances bone matrix production (10, 11). In addition, IGF1 is being recognized as a critical factor for bone cell survival (12)(13)(14). Finally, IGF1 also appears to regulate bone resorption, either directly or through its actio...

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We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal cranial dimensions, defective dental ameloblasts, and nasal septal deviation, consistent with some of the features of human Costello syndrome. These mice developed papillomas and angiosarcomas, which were associated with Hras G12V allelic imbalance and augmented Hras signaling. Endogenous expression of Hras G12V was also associated with a higher mutation rate in vivo. Tumor initiation by Hras G12V likely requires augmentation of signal output, which in papillomas and angiosarcomas is achieved via increased Hras-gene copy number, which may be favored by a higher mutation frequency in cells expressing the oncoprotein.allele copy number ͉ angiosarcoma ͉ Costello syndrome ͉ papilloma ͉ senescence

Interferon-alpha (IFNα) is the cornerstone therapeutic agent for chronic hepatitis C virus (HCV) infection. Prospective studies have shown that up to 15% of HCV patients receiving interferon alpha develop clinical thyroid disease, and up to 40% become thyroid antibody positive. In some cases interferon induced thyroiditis (IIT) may result in discontinuation of interferon therapy; thus, IIT represents a major clinical problem for hepatitis C patients receiving IFNα therapy. Recently, the mechanisms leading to the development of IIT are beginning to be unraveled. It is now clear that the hepatitis C Virus (HCV) itself plays a role in the disease. Moreover, recent data suggest the IFNα precipitates thyroiditis by both immune modulatory mechanisms and direct thyroid toxic effects. Genetic factors also play a major role in the etiology of IIT. IIT can manifest both as clinical autoimmune thyroiditis (i.e. Hashimoto's thyroiditis and Graves' disease) and as non-autoimmune thyroiditis (i.e. destructive thyroiditis). Early detection and therapy of these conditions is important in order to avoid complications of thyroid disease such as cardiac arrhythmias. In this review, we will review the epidemiology and clinical manifestations of IIT as well as the mechanisms causing IIT, focusing on the role of hepatitis C virus.

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