Inflammatory cytokines and the GH/IGF-I axis: Novel actions on bone growth

The Roslin Institute and Royal School of Veterinary Studies, The University of Edinburgh, Midlothian, UK.
Cell Biochemistry and Function (Impact Factor: 2.01). 04/2009; 27(3):119-27. DOI: 10.1002/cbf.1551
Source: PubMed


Longitudinal bone growth is a tightly regulated process that relies on complex synchronized mechanisms at the growth plate. Chronic paediatric inflammatory diseases are well accepted to lead to growth retardation and this is likely due to raised inflammatory cytokine levels and reduced growth hormone (GH)/insulin-like growth factor-1 (IGF-I) signalling. The precise cellular mechanisms responsible for this inhibition are unclear and therefore in this article, we will review the potential interactions between inflammatory cytokines and the GH/IGF-I axis in the regulation of bone growth. In particular, we will emphasis the potential contribution of the suppressors of cytokine signalling (SOCS) proteins, and in particular SOCS2, in mediating this process.

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    • "This observation is in agreement with previous reports where mice missing the Socs2 gene have increased linear bone growth due to increased signaling through the GHR (Metcalf et al., 2000; Greenhalgh et al., 2005; MacRae et al., 2009). Although, it is well recognized that GH signaling is also modulated by CIS and SOCS1 and 3 we have reported previously that GH does not stimulate chondrocyte SOCS 1 or 3 protein levels (Pass et al., 2009, 2012). Furthermore, Socs1 -/and Socs3 -/-mice are perinatal and embryonic lethal, respectively and little data exists on their ability to regulate bone growth (Greenhalgh and Alexander, 2004). "
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    ABSTRACT: Growth hormone (GH) signalling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver-derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here we investigate linear growth in Suppressor of Cytokine Signalling (SOCS2)-2 knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (p < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12-day-period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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