Endocrine Abstracts (2013) 31 P4

Contribution to bone mass and strength of osteoblast GH actions that are independent of local IGF1 production: lessons from the SOCS2 knockout mouse

Ross Dobie1, Vicky MacRae1, Carmen Huesa1, Rob van’t Hof2, Faisal Ahmed3 & Colin Farquharson1

1The Roslin Institute, University of Edinburgh, Edinburgh, UK; 2Centre for Molecular Medicine, University of Edinburgh, Edinburgh, UK; 3Section of Child Health, School of Medicine, University of Glasgow, Glasgow, UK.

GH is anabolic to the skeleton but its mode of action is unclear. Clues are available from the study of the suppressor of cytokine signalling-2 (SOCS2) KO mouse which has increased bone mass despite normal systemic IGF1 levels. Whilst suggesting direct GH effects on bone forming osteoblasts the precise signalling mechanisms remain unclear. The aims of this study were, therefore, to further detail the bone phenotype of SOCS2 KO mice and determine if GH promotes bone mass by mechanisms that are dependent or independent of osteoblast IGF1 production.

All SOCS2 KO mice had increased trabecular BV/TV (P<0.05) and cortical BV (P<0.05) as assessed by μCT. The cortex was thicker only in male SOCS2 KO mice and this was associated with increased breaking strength (P<0.05) as determined by three-point bending. IGF1 and IGFBP3 mRNA expression levels were similar between bone and liver samples of SOCS2 KO and WT mice supporting a local, IGF1 independent, GH mechanism responsible for the noted increased bone mass. In vitro mechanistic studies (immunoblotting and immunocytochemistry) indicated that in WT osteoblasts, SOCS2 (but not SOCS1 or 3) transcript and protein expression increased in response to GH. Also, GH promoted greater STATs one, three and five phosphorylation in SOCS2 KO calvarial osteoblasts than in WT cells. Overexpression of SOCS2 in MC3T3 osteoblast-like cells resulted in decreased STAT 5 signalling following GH challenge. This GH mediated increased STAT signalling in SOCS2 KO cells resulted in, as expected, elevated IGF1 mRNA expression (P<0.05) but the magnitude of the increase was similar to that noted in WT cells. These data confirm our in vivo observations.

These studies emphasise the critical role for SOCS2 in controlling GH anabolic bone effects. They also confirm the functional contribution to bone mass of osteoblast GH actions that are independent of local IGF1 production.

DOI: 10.1530/endoabs.31.P4

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