SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

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 has 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 of GH 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 GH stimulated chondrocyte STATs-1, -3 and -5 phosphorylation was increased in SOCS2(-/-) chondrocytes but not in cells over-expressing SOCS2. This increased chondrocyte STAT signalling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2(-/-) embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data; bone growth rates, growth plate widths and chondrocyte proliferation were all increased in SOCS2(-/-) 6-week old mice as was the number of phosphorylated STAT-5 positive hypertrophic chondrocytes. The SOCS2(-/-) mouse represents a valid model for studying the local effects of GH and IGF-1 on bone growth. (c) 2012 American Society for Bone and Mineral Research.