title: Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent.
abstract: Cocaine- and amphetamine-regulated transcript (CART) has emerged as a neurotransmitter and hormone that has been implicated in many processes including food intake, maintenance of body weight, and reward, but also in the regulation of bone mass. CART-deficient mice are characterized by an osteoporotic phenotype, whereas female transgenic mice overexpressing CART display an increase in bone mass. Here we describe experiments that show that peripheral subcutaneous sustained release of different CART peptide isoforms for a period up to 60 days increased bone mass by 80% in intact mice. CART peptides increased trabecular bone mass, but not cortical bone mass, and the increase was caused by reduced osteoclast activity in combination with normal osteoblast activity. The observed effect on bone was gender-specific, because male mice did not respond to treatment with CART peptides. In addition, male transgenic CART overexpressing mice did not display increased bone mass. Ovariectomy (OVX) completely abolished the increase of bone mass by CART peptides, both in CART peptide-treated wild-type mice and in CART transgenic mice. The effect of CART peptide treatment on trabecular bone was not mediated by 17β-estradiol (E(2)) because supplementation of OVX mice with E(2) could not rescue the effect of CART peptides on bone. Together, these results indicate that sustained release of CART peptides increases bone mass in a gender-specific way via a yet unknown mechanism that requires the presence of the ovary.
authors: Merck Sharp & Dohme Research Laboratories, Women's Health Department, Oss, The Netherlands. han.gerrits@merck.com
authors: Han
authors: H
authors: Gerrits
authors: Nicole Ec
authors: NE
authors: Bakker
authors: Cindy Jm
authors: CJ
authors: van de Ven-de Laat
authors: Freek Gm
authors: FG
authors: Bourgondien
authors: Carolien
authors: C
authors: Peddemors
authors: Ralph Hgm
authors: RH
authors: Litjens
authors: Han J
authors: HJ
authors: Kok
authors: Gerard Mt
authors: GM
authors: Vogel
authors: Magda Am
authors: MA
authors: Krajnc-Franken
authors: Jan A
authors: JA
authors: Gossen
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000000981:diagnostic imaging / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006062:Gonadotropins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010053:Ovary / Q000187:drug effects*; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012727:Sex Characteristics; D055114:X-Ray Microtomography; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D006062:Gonadotropins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D004958:Estradiol