-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. -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, -MSH may act directly on the skeleton, a question addressed by the present studies. In primary cultures of osteoblasts and chondrocytes, -MSH dose-dependently (10^-9M ) stimulated cell proliferation. In bone marrow cultures, -MSH (>10^-9M) stimulated osteoclastogenesis. Systemic administration of -MSH to mice (20 injections of 4.5 µg/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 indices of trabecular bone, assessed by phase-contrast x-ray imaging, confirmed the bone loss. It is concluded that -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 -MSH effects elsewhere, such as the adipocyte, pancreatic beta cell, or central nervous system.