α-melanocyte-stimulating hormone is a novel regulator of bone

alpha-Melanocyte-stimulating hormone (alpha-MSH), a 13-amino acid peptide produced in the brain and pituitary gland, is a regulator of appetite and body weight, and its production is regulated by leptin, a factor that affects bone mass when administered centrally. alpha-MSH acts via melanocortin receptors. Humans deficient in melanocortin receptor 4 (MC4-R) have increased bone mass, and MC4-R has been identified in an osteoblast-like cell line. Thus alpha-MSH may act directly on the skeleton, a question addressed by the present studies. In primary cultures of osteoblasts and chondrocytes, alpha-MSH dose dependently (greater than or equal to10(-9) M) stimulated cell proliferation. In bone marrow cultures, alpha-MSH (>10(-9) M) stimulated osteoclastogenesis. Systemic administration of alpha-MSH to mice ( 20 injections of 4.5 mug/day) decreased the trabecular bone volume in the proximal tibiae from 19.5 +/- 1.8 to 15.2 +/- 1.4% (P = 0.03) and reduced trabecular number (P = 0.001). Radiographic indexes of trabecular bone, assessed by phase-contrast X-ray imaging, confirmed the bone loss. It is concluded that alpha-MSH acts directly on bone, increasing bone turnover, and, when administered systemically, it decreases bone volume. The latter result may also be contributed to by alpha-MSH effects elsewhere, such as the adipocyte, pancreatic beta-cell, or central nervous system.