The role of suppressor of cytokine signalling-2 in endochondral bone growth.
PhD thesis, University of Glasgow.
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Suppressor of Cytokine Signalling-2 (SOCS2) is a negative regulator of growth hormone (GH) signalling and bone growth via inhibition of the JAK/STAT pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2-/- mice which have normal systemic IGF-1 levels. The local effects of GH on bone growth are equivocal and therefore this study aimed to understand better the SOCS2 signalling mechanisms mediating the local actions on epiphyseal chondrocytes and bone growth.
SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes following GH challenge; and gain-and-loss of function studies indicated that SOCS2 acts to negatively regulate GH stimulated chondrocyte STAT phosphorylation. This was confirmed by the observation that GH stimulates the longitudinal growth of cultured SOCS2-/- embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this; bone growth rates, growth plate zone widths and chondrocyte proliferation were all increased in 6-week old SOCS2-/- mice as was the number of phosphorylated STAT-5 positive hypertrophic chondrocytes. The results of these studies indicate that the SOCS2-/- mouse represents a valid model for studying the local effects of GH and IGF-1 on bone growth.
Chronic paediatric inflammatory diseases are well accepted to lead to growth retardation and this is likely due to raised inflammatory cytokine levels and reduced GH/IGF-1 signalling. Whilst SOCS2 was not found to be increased in response to inflammatory cytokines, SOCS2-/- mice were
protected from LPS-induced growth retardation indicating that SOCS2 antagonists may help ameliorate the negative effects of chronic inflammation on growth.
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