The effect of alphaMSH analogues on rat bones.
Melanocortin is the downstream mediator of leptin signaling and absence of leptin signaling in ob/ob and db/db mice revealed the enhancement of bone formation through the central regulation. While alpha-melanocyte-stimulating hormone (alphaMSH) inhibits the secretion of interleukin-1alpha and tumor necrosis factor-alpha from the inflammatory cells, alphaMSH can also enhance clonal expansion of pro B cells linked to stimulation of osteoclastogenesis. Therefore, we tested the effect of melanocortin on bones. alphaMSH analogues [(6)His]alphaMSH-ND and [(6)Asn]alphaMSH-ND were synthesized and the radio-ligand receptor binding- and cyclic AMP generating activity were analyzed in China Hamster Ovary cell line over- expressing melanocortin receptors. The EC(50) of [(6)His]alphaMSH-ND measured from melanocortin-1, 3, 4 and 5 receptors were 0.008 +/- 0.0045, 1.523 +/- 0.707, 0.780 +/- 0.405, and 250.320 +/- 42.234 nM, respectively, and the EC(50) of [(6)Asn]alphaMSH-ND were 16.8 +/- 6.94, 271.8 +/- 21.95, 8.0 +/- 1.21, and 1132.5 +/- 635.46 nM, respectively. Four weeks after the subcutaneous injection of the analogues, the body weights in the [(6)His]alphaMSH-ND and the [(6)Asn]alphaMSH-ND treated groups (346.0 +/- 20.63 g vs. 350.0 +/- 13.57 g) were lower than that of the vehicle treated group (375.8 +/- 17.31 g, p < 0.05). There was no difference in the total femoral BMD measured by dual x-ray absorptiometry among the three groups. Among the three groups, there were no differences in the total numbers of crystal violet positive- or alkaline phosphatase positive colonies, in the expression of Receptor Activator of Nuclear Factor Kappa-B ligand on the tibia and the total number of multinucleated osteoclast-like cells differentiated from primary cultured bone marrow cells. From the above results, no evidence of bone gain or loss was found after treatment of the alphaMSH analogues peripherally.
Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul 120-752, Korea. lsk@yumc.yonsei.ac.kr
Sung-Kil
SK
Lim
Song-Zhe
SZ
Li
Yumie
Y
Rhee
Sang Su
SS
Chung
Yong-Jun
YJ
Jin
Jong In
JI
Yook
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004435:Eating / Q000187:drug effects; D008297:Male; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018043:Receptors, Corticotropin / Q000502:physiology; D044101:Receptors, Melanocortin; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology*
D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000521:alpha-MSH; D000242:Cyclic AMP