Increased bone mass , altered trabecular architecture and modified growth plate organization in the growing skeleton of SOCS 2 deficient mice

Suppressor of Cytokine Signaling-2 (SOCS2) negatively regulates the signal transduction of several cytokines. Socs2 mice show increased longitudinal skeletal growth associated with deregulated GH/IGF-1 signaling. The present study examined the role of SOCS2 in endochondral ossification and trabecular and cortical bone formation, and investigated whether pro-inflammatory cytokines associated with pediatric chronic inflammatory disorders mediate their effects through SOCS2. 7-week-old Socs2 mice were heavier (27%; P<0.001) and longer (6%; P<0.001) than wild-type mice. Socs2 tibiae were longer (8%; P<0.001) and broader (18%; P<0.001) than that of wild-type mice, and the Socs2 mice had wider growth plates (24%; P<0.001) with wider proliferative and hypertrophic zones (10% (P<0.05) and 14% (P<0.001) respectively). Socs2 mice showed increased total cross-sectional bone area (16%: P<0.001), coupled to increased total tissue area (17%; P<0.05) compared to tibia from wild-type mice. Socs2 mice showed increased percent bone volume (101%; P<0.001), trabecular number (82%; P<0.001) and trabecular thickness (11%; P<0.001), with associated decreases in trabecular separation (19%; P<0.001). TNFα exposure to growth plate chondrocytes for 48h increased SOCS2 protein expression. Growth of metatarsals from 1-day-old Socs2 and Socs2 mice, as well as expression of Aggrecan, Collagen Type II and Collagen Type X, were inhibited by TNFα, with no effect of genotype. Our data indicate that physiological levels of SOCS2 negatively regulate bone formation and endochondral growth. Our results further suggest that pro-inflammatory cytokines mediate their inhibitory effects on longitudinal bone growth through a mechanism that is independent of SOCS2. Introduction Suppressor of Cytokine Signaling (SOCS) proteins are transcribed in response to cytokine stimulation and utilise various receptor-mediated mechanisms to down-regulate cytokine signal transduction pathways (Leroith and Nissley 2005; Rico-Bautista et al. 2006). The molecular mechanisms of SOCS action involve inhibiting Janus kinase (JAK) activity, blocking signal transducers and activators of transcription (STAT) binding sites on cytokine receptors or promoting the degradation of specific signaling proteins. SOCS proteins thereby form part of a classical negative feedback circuit to avoid the detrimental consequences of excessive stimulation. (Krebs and Hilton 2001). It has been demonstrated that SOCS2, one of eight SOCS family members (Yoshimura et al. 2007), is also an important regulator of somatic growth through its regulation of GH/IGF-I signaling. SOCS2 is able to bind the GH receptor through tyrosine residues Y595 and Y487 (Greenhalgh et al. 2005), and since Y595 is a known binding site for STAT5, SOCS2 may therefore block access of STAT5 to the activated GH receptor (Smit et al. 1996), although this has recently been questioned (Uyttendaele et al. 2007). SOCS2 can also inhibit JAK2 tyrosine phosphorylation (Ram and Waxman 1999), suggesting that SOCS2 may inhibit GH signaling by directly binding to JAK2. SOCS2 may bind to the IGF-I receptor (Dey et al. 1998) and inhibit IGF-I induced STAT3 activation (Zong et