The effect of gh and igf1 on linear growth and skeletal development and their modulation by socs proteins

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REVIEW The effect of GH and IGF1 on linear growth and skeletal development and their modulation by SOCS proteins
S F Ahmed and C Farquharson1
Developmental Endocrinology Research Group, Division of Developmental Medicine, Department of Child Health, Royal Hospital For Sick Children, University of Glasgow, Yorkhill, Glasgow G3 8SJ, UK
1

Bone Biology Group, Division of DevelopmentalBiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Edinburgh EH25 9PS, UK

(Correspondence should be addressed to S F Ahmed; Email: s.f.ahmed@clinmed.gla.ac.uk)

Abstract
Circulating signalling proteins have often been divided into hormones and cytokines, but it is increasingly being recognised that these substances have a number ofcommon characteristics and mechanisms of action. This is clearly illustrated by the suppressor of cytokine signalling (SOCS) proteins which are increasingly seen as a central component of the regulation of the action of hormones and cytokines that signal through the cytokine receptor complex. The SOCS protein family is probably more extensive than currently recognised; its members may havedifferential tissue expression and their potency for suppressing cytokine signalling may vary. Recent knockout and transgenic studies in mice have highlighted the role that these proteins play in growth and skeletal development as well as in inflammation. Chronic inflammation is associated with altered growth and skeletal development, and it is possible that SOCS proteins may have an important role to play inmediating these effects.
Journal of Endocrinology (2010) 206, 249–259

Introduction
Linear growth and skeletal development are tightly regulated processses that are highly dependent on GH signalling and action. Clinical studies have shown that growth and skeletal development are impaired during periods of uncontrolled chronic inflammation which is often associated with altered systemic andlocal cytokine milieu. The mechanisms by which these inflammatory cytokines modulate linear growth and skeletal development are poorly understood, but an involvement of members of the suppressor of cytokine signalling (SOCS) family has been proposed. This review will first describe SOCS proteins and the effects of the GH/insulin-like growth factor 1 (IGF1) axis on linear growth and skeletal developmentbefore describing the evidence that highlights the role of SOCS proteins in controlling this axis as well as in skeletal development.

Cytokine signalling
Cellular responses to cytokine stimulation depend on the type of cytokine and the nature of the target cell, and include immune function, inflammation, and cell proliferation and differentiation. The interaction between a cytokine and itsJournal of Endocrinology (2010) 206, 249–259 0022–0795/10/0206–249 q 2010 Society for Endocrinology

receptor induces receptor dimerisation or oligomerisation, which results in the juxtaposition of a group of proteins that are members of the Janus kinase (JAK) family of protein tyrosine kinases – JAK1, JAK2, JAK3 and TYK2 ( Ihle & Kerr 1995). These can cross-phosphorylate, causing enzymaticactivation of the cytokine receptor. GH, prolactin and leptin are just some of the ligands that signal through these same receptors and along with other cytokines have their own specific preferential JAKs. A key target of JAK activity is the cytoplasmic domain of the cytokine receptor, which becomes tyrosine phosphorylated at multiple residues, creating docking sites for signalling proteins containingSrc homology 2 (SH2) or phosphotyrosine-binding domains. It is likely that some downstream signalling pathways are common to all cytokine receptors and some are specific for individual cytokine receptors (Leaman et al. 1996). The association between signalling proteins and cytokine receptors serves to initiate multiple signalling pathways, such as those regulated by Ras sarcoma proteins (RAS),...