Abstract
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.
Highlights
Growth hormone (GH) is a key regulator of postnatal skeletal development; its mode of action remains unclear (Slootweg 1993, Ohlsson et al 1998)
The overgrowth phenotype observed in Socs2K/K mice exhibits several features of deregulated GH signalling, including collagen accumulation in the dermis, and the decreased production of major urinary proteins (Metcalf et al 2000, Greenhalgh et al 2005)
Socs2K/K mice are indistinguishable from WT littermates until 4–6 weeks, which coincides with the period of peak GH activity that occurs between postnatal days 20 and 40 (Wang et al 2004)
Summary
Growth hormone (GH) is a key regulator of postnatal skeletal development; its mode of action remains unclear (Slootweg 1993, Ohlsson et al 1998). It is likely to involve both endocrine (systemic) actions via hepatic insulin-like growth factor 1 (IGF1) production and autocrine/paracrine (local) actions via the osteoblast. Local GH actions may be indirect (IGF1 dependent) or direct (IGF1 independent) (Isgaard et al 1986, 1989, Le Roith et al 2001). The intimate relationship between GH and IGF1 makes it difficult to deduce the relative contributions of systemic and locally derived IGF1 to bone accrual. While GhrK/K mice have recognised changes in skeletal mass and architecture, these effects may be mediated through IGF1, as GhrK/K mice have reduced systemic IGF1 levels (Sims et al 2000, Sjogren et al 2000). Global Igf1K/K and osteoblast-specific Igf1rK/K mice have altered bone architecture and diminished osteoid mineralisation (Bikle et al 2001, Zhang et al 2002)
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