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

The suppressor of cytokine signalling (SOCS)-2 knockout mouse (Socs2-/-) is characterised by an overgrowth phenotype due to enhanced growth-hormone (GH) signalling. The objective of this study was to define the Socs2-/- bone phenotype and determine if GH promotes bone mass via insulin-like growth-factor (IGF)-1 dependent mechanisms. Despite no elevation in systemic IGF-1, 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, indicating that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in Socs2-/- osteoblasts and bone, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signaling. 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 from 6-week-old Socs2-/- mice. These studies emphasise the critical role for 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 IGF-1 production in vivo.