Endocrine Abstracts (2013) 31 P2

Increased linear bone growth in SOCS2 knockout mice in response to GH is independent of systemic or local IGF1

Ross Dobie1, Vicky MacRae1, Chloe Pass1, Seema Jasim1, Faisal Ahmed2 & Colin Farquharson1

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

Introduction: GH signalling is essential for post-natal linear bone growth. The systemic/local mechanisms responsible for GH action remain unclear as the importance of liver derived IGF1 on linear growth has recently been challenged.

Aim: To unravel the underlying mechanisms of linear bone growth we exploited the suppressor of cytokine signalling-2 (SOCS2) KO mice which have enhanced linear growth despite normal systemic IGF1 and GH levels.

Methods: Growth plates were micro-dissected from WT and SOCS2 KO bone and IGF1 levels assessed by RT-qPCR. Embryonic day 17 metatarsals were cultured from both WT and SOCS2 KO mice in the presence of GH in order to assess downstream signalling and IGF1 expression.

Results: Our present in vivo data revealed no downstream increase in Igf1 expression in growth cartilage of WT and SOCS2 KO mice. These data were extended by ex-vivo embryonic metatarsal experiments. In response to GH, wild-type (WT) bones expressed increased SOCS2 (but not SOCS1 or 3) transcript levels but STAT5 phosphorylation was profoundly less than that noted in similarly treated SOCS2 null metatarsals. This confirms and extends our previous in vitro chondrocyte data. Increased STAT5 activation of SOCS2 metatarsals following GH challenge was associated with increased linear growth over an 8-day-period whereas the growth of GH treated WT bones remained unchanged. This increased growth of SOCS2 null bones in response to GH was not, however, accompanied by greater IGF1 and IGFBP3 transcript levels suggestive of IGF1 independent mechanisms. Moreover, GH remained stimulatory to SOCS2 bone growth in the presence of an IGF1 receptor inhibitor (NVP-AEW541).

Discussion: These studies emphasise the importance of SOCS2 in the regulation of GH stimulation of linear bone growth and indicate that GH can enhance linear growth by initiating molecular pathways intrinsic to the growth plate that are independent of local IGF1 production.

DOI: 10.1530/endoabs.31.P2

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