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      Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2 −/− mice


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          The suppressor of cytokine signalling ( Socs2 −/− )-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2 −/− bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2 −/− mice following GH treatment was associated with increased cortical bone area (Ct.Ar) ( P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2 −/− mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2 −/− mice had increased Ct.Ar ( P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2 −/− mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2 −/− osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2 −/− mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.

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          Normal growth and development in the absence of hepatic insulin-like growth factor I.

          The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I.
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            Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization.

            To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cre-mediated 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.
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              Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice.

              The body growth of animals is regulated by growth hormone and IGF-I. The classical theory of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice demonstrated complete inactivation of the IGF-I gene in the hepatocytes. Although the liver accounts for less than 5% of body mass, the concentration of IGF-I in the serum was reduced by 75%. This finding confirms that the liver is the principal source of IGF-I in the blood. However, the reduction in serum IGF-I concentration had no discernible effect on postnatal body growth. We conclude that postnatal body growth is preserved despite complete absence of IGF-I production by the hepatocytes.

                Author and article information

                J Endocrinol
                J. Endocrinol
                The Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                October 2014
                29 July 2014
                : 223
                : 1
                : 93-106
                [1]Division of Developmental Biology, The Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush , Edinburgh, Midlothian, EH25 9RG, Scotland, UK
                [1 ]Institute of Ageing and Chronic Disease, University of Liverpool , Daulby Street, Liverpool, L69 3GA, UK
                [2 ]Developmental Endocrinology Research Group, School of Medicine, University of Glasgow , Yorkhill, Glasgow, G3 8SJ, Scotland, UK
                Author notes
                Correspondence should be addressed to R Dobie; Email: ross.dobie@ 123456roslin.ed.ac.uk
                © 2014 The authors

                This work is licensed under a Creative Commons Attribution 3.0 Unported License

                : 30 June 2014
                : 29 July 2014

                Endocrinology & Diabetes
                Endocrinology & Diabetes
                gh/igf1, bone, socs2, osteoblast


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