A possible role for melanocortin peptides in longitudinal growth.

Clinical and in vitro data suggest a link between the elevation of the melanocortin peptide, ACTH, and longitudinal growth. Overproduction of ACTH in familial glucocorticoid deficiency (FGD) is associated with increased growth and ACTH increases the differentiation of chondrocytes along the endochondral pathway in vitro. Using the leptin-deficient obese (ob/ob) mouse along with lean control littermates (n = 9-10), we investigated the effects of adrenalectomy (ADX)-induced elevated ACTH with and without peripheral administration of the MC3-R-specific agonist, gamma2-melanocyte stimulating hormone (gamma2-MSH), on longitudinal growth. Naso-anal and tibial growth were measured together with growth plate parameters; both total and zonal heights together with the proliferative index. Data were analyzed using two-way ANOVA with post hoc comparisons made using the Bonferroni correction. ADX significantly increased naso-anal length in lean mice and ADX plus gamma2-MSH administration significantly increased naso-anal length above ADX alone in ob/ob mice. gamma2-MSH administration to ADX lean and ob/ob mice significantly increased tibial length. In ob/ob mice, these changes occurred in the context of reduced food intake. Analysis of total and zonal growth plate heights suggest an increase in hypertrophic differentiation and an overall increase in growth plate turnover in ADX lean and ob/ob mice. These in vivo data show that ADX enhances linear growth and the results of gamma2-MSH treatment suggest that the melanocortin system plays a role in linear growth.

[1]  J. Aloia,et al.  Adrenocorticotropin evokes transient elevations in intracellular free calcium ([Ca2+]i) and increases basal [Ca2+]i in resting chondrocytes through a phospholipase C-dependent mechanism. , 2005, Endocrinology.

[2]  R. Bollag,et al.  Multiple melanocortin receptors are expressed in bone cells. , 2005, Bone.

[3]  H. Schiöth,et al.  α-MSH and γ-MSH inhibit IL-1β induced activation of the hypothalamic–pituitary–adrenal axis through central melanocortin receptors , 2004, Regulatory Peptides.

[4]  L. Jacobson,et al.  Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight, and hippocampal glucocorticoid receptors in male C57BL/6 mice. , 2004, Endocrinology.

[5]  J. Aloia,et al.  ACTH enhances chondrogenesis in multipotential progenitor cells and matrix production in chondrocytes. , 2004, Bone.

[6]  M. Phillip,et al.  Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth. , 2004, Endocrinology.

[7]  H. Schiöth,et al.  alpha-MSH and gamma-MSH inhibit IL-1beta induced activation of the hypothalamic-pituitary-adrenal axis through central melanocortin receptors. , 2004, Regulatory peptides.

[8]  S. Amiel,et al.  ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans. , 2004, The Journal of endocrinology.

[9]  Sheng Bi,et al.  Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[10]  S. Murray,et al.  Effects of dietary restriction on total body, femoral, and vertebral bone in SENCAR, C57BL/6, and DBA/2 mice. , 2003, Metabolism: clinical and experimental.

[11]  R. Berger,et al.  Short-term glucocorticoid treatment of prepubertal mice decreases growth and IGF-I expression in the growth plate. , 2003, The Journal of endocrinology.

[12]  R. Cone,et al.  Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. , 2003, The Journal of clinical investigation.

[13]  D. Chrysis,et al.  Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes. , 2003, The Journal of endocrinology.

[14]  B. Lanske,et al.  PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. , 2002, Development.

[15]  E. Schwarz,et al.  Growth plate chondrocyte maturation is regulated by basal intracellular calcium. , 2002, Experimental cell research.

[16]  M. Phillip,et al.  Leptin Acts as a Growth Factor on the Chondrocytes of Skeletal Growth Centers , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  Herbert Herzog,et al.  Y4 receptor knockout rescues fertility in ob/ob mice. , 2002, Genes & development.

[18]  S. O’Rahilly,et al.  Differential effects of α-, β- and γ2-melanocyte-stimulating hormones on hypothalamic neuronal activation and feeding in the fasted rat , 2001, Neuroscience.

[19]  M. Low,et al.  The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis , 2001, International Journal of Obesity.

[20]  S. Lightman,et al.  Resistance to glucocorticoid feedback in obesity. , 2001, The Journal of clinical endocrinology and metabolism.

[21]  W. Wilkison,et al.  Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. , 2001, Physiological genomics.

[22]  M. Roudbaraki,et al.  Stimulation of Intracellular Free Calcium in GH3 Cells byγ 3-Melanocyte-Stimulating Hormone. Involvement of a Novel Melanocortin Receptor? , 2001, Endocrinology.

[23]  S. O’Rahilly,et al.  Differential effects of alpha-, beta- and gamma(2)-melanocyte-stimulating hormones on hypothalamic neuronal activation and feeding in the fasted rat. , 2001, Neuroscience.

[24]  J. Roberts,et al.  Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice. , 2000, Diabetes.

[25]  P. Clayton,et al.  Tall stature in familial glucocorticoid deficiency , 2000, Clinical endocrinology.

[26]  C. Mantzoros,et al.  Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. , 2000, American journal of physiology. Endocrinology and metabolism.

[27]  Yue Feng,et al.  Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass , 2000, Nature Genetics.

[28]  C. Steppan,et al.  Leptin is a potent stimulator of bone growth in ob/ob mice , 2000, Regulatory Peptides.

[29]  R. Cone.  The Melanocortin-4 Receptor , 2000 .

[30]  S. Solomon.  POMC‐Derived Peptides and Their Biological Action , 1999, Annals of the New York Academy of Sciences.

[31]  A. Clark,et al.  Adrenocorticotropin insensitivity syndromes. , 1998, Endocrine reviews.

[32]  R. Erben,et al.  Embedding of Bone Samples in Methylmethacrylate: An Improved Method Suitable for Bone Histomorphometry, Histochemistry, and Immunohistochemistry , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[33]  R. Cone,et al.  Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by α- and γ-Melanocyte-Stimulating Hormones , 1996, The Journal of Neuroscience.

[34]  T. Wronski,et al.  Skeletal response to corticosteroid deficiency and excess in growing male rats. , 1996, Bone.

[35]  A. Dunn,et al.  Effect of dexfenfluramine on metabolic and neurochemical measures in restraint-stressed ob/ob mice , 1995, Physiology & Behavior.

[36]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[37]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[38]  Teri A. Crosby,et al.  How to Detect and Handle Outliers , 1993 .

[39]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  G. Bray,et al.  Adrenalectomy and food restriction in the genetically obese (ob/ob) mouse. , 1984, The American journal of physiology.

[41]  P. Naeser.  Disappearance of 3h-corticosterone from the serum of obese-hyperglycemic mice (gene symbol ob). , 1975, Acta physiologica Scandinavica.

[42]  J. Plager,et al.  CORTISOL METABOLISM IN OBESITY. , 1964, The Journal of clinical endocrinology and metabolism.

[43]  L. C. Wyman,et al.  Changes in width of uncalcified tibial epiphyseal cartilage of the rat following adrenalectomy and gonadectomy. , 1954, The American journal of physiology.