Inflammatory cytokines and the GH/IGF-I axis: novel actions on bone growth.
ABSTRACT 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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ABSTRACT: The suppressor of cytokine signalling (SOCS)-2 knockout mouse (Socs2-/-) is characterised by an overgrowth phenotype due to enhanced growth-hormone (GH) signalling. The objective of this study was to define the Socs2-/- bone phenotype and determine if GH promotes bone mass via insulin-like growth-factor (IGF)-1 dependent mechanisms. Despite no elevation in systemic IGF-1, increased body weight in 4-week-old Socs2-/- mice following GH treatment was associated with increased cortical bone area (Ct.Ar)(p<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2-/- mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2-/- mice had increased Ct.Ar(p<0.05) and thickness associated with increased strength. Despite this there was no elevation in hepatic Igf1 expression, indicating that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in Socs2-/- osteoblasts and bone, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signaling. Although an increase in Igf1 expression was observed in Socs2-/- osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples from 6-week-old Socs2-/- mice. These studies emphasise the critical role for SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual which maybe via mechanisms that are independent of IGF-1 production in vivo.Journal of Endocrinology 09/2014; · 3.59 Impact Factor
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ABSTRACT: Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment.Nature Reviews Gastroenterology & Hepatology 06/2014; · 10.43 Impact Factor
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ABSTRACT: Background & objectives: After menopause in women, loss of bone density increases rapidly with estrogen deficiency. Evidence has revealed that this deficiency may be directly correlated with growth hormone (GH) level declining with age. The present study was designed to evaluate the age dependant patterns of GH, insulin-like growth factor-1 (IGF1-1) and insulin-like growth factor binding protein-3 (IGFBP-3) endogenous secretion in postmenopausal women. Methods: During this prospective study in a 12-month period, 150 postmenopausal women were enrolled who were referred to the densitometry unit of bone research centre of Tabriz University of Medical Sciences for assessing bone mineral density. Serum levels of basal and clonidine stimulated GH were measured using radioimmunoassay while IGF-1 and IGFBP-3 were measured by ELISA. Post stimulation over 3 to 6 fold increase in GH over the baseline level was considered normal response and less increase was considered abnormal. Results: There were no significant differences in the mean levels of GH0, GH60 and GH90 in different age groups of postmenopausal women. No significant difference in the mean IGFBP-3 and IGF-1 levels was seen in different age groups of postmenopausal women. The number of postmenopausal women with abnormal response to stimulation by clonidine in 61-70 and > 70 yr age groups was higher than in other groups (P< 0.05). Interpretation & conclusions: Despite the higher rate of abnormal response to stimulation by clonidine in women aged more than 60 yr, the current study showed no significant correlation between age, and the basal and stimulated GH secretion rate and serum levels of IGF-1 and IGFBP-3 in postmenopausal women.The Indian journal of medical research. 04/2014; 139(4):598-602.