Many growth deficiencies are currently treated with Growth Hormone (GH), including those with an etiology other than GH deficiency e.g. idiopathic short stature. In these cases the efficacy of treatment has been questioned and the high cost has to be carefully weighed against the significance of the outcome. The overall goal of this project is to identify a mechanism of linear growth that is independent of the Growth Hormone/Insulin-like Growth Factor-I (GH/IGF-I) axis. Examination of cases of enhanced linear growth in the absence of abnormalities in the GH/IGF-I axis, such as Familial Glucocorticoid Deficiency and obesity suggest a link between adrenocorticotropin hormone (ACTH) and the regulation of endochondral ossification; in these cases ACTH exposure is elevated in the context of lowered glucocorticoid. ACTH, a member of the melanocortin family of proteins, can exert its effects through all five of the melanocortin receptors (MCR's). This proposal will test the hypothesis that ACTH, signaling through the melanocortin-3 receptor (MC3-R) plays a role in linear growth. The project has two specific aims. (1) To determine the effect of elevated endogenous ACTH and/or exogenous gamma2-MSH on linear growth in the context of low glucocorticoid. The effects of gamma2-Melanocyte stimulating hormone (gamma2-MSH), an agonist of the MC3-R, on the length and longitudinal growth rate of adrenalectomized obese and normal mice will be evaluated. (2) To determine the effect of elevated endogenous ACTH and/or exogenous gamma2-MSH on Indian hedgehog (Ihh) and parathyroid related protein (PTHrP) regulation of linear growth in the context of low glucocorticoid. Immunohistochemistry will be used to evaluate expression differences of parathyroid hormone/parathyroid related protein receptor (PPR), parathyroid-related protein (PTHrP), Indian hedgehog (Ihh), Type II collagen and Type X collagen in the growth plate of adrenalectomized obese and normal mice +/- treatment with gamma2-MSH. If this hypothesis is correct, it could lead to the development of supplements to GH in the treatment of growth deficiencies.
| Yeh, James K; Evans, Jodi F; Niu, Qing-Tian et al. (2006) A possible role for melanocortin peptides in longitudinal growth. J Endocrinol 191:677-86 |
