Adiponectin has until now been considered to be synthesized and secreted exclusively by the adipose tissue, and is reported to influence energy homeostasis and insulin sensitivity. It is also known that body weight is positively correlated with increased bone mineral density and decreased fracture risk. The mechanisms explaining this relation, however, are not completely understood. We report a link between adiponectin and bone homeostasis by demonstrating transcription, translation, and secretion of adiponectin, as well as expression of its receptors, AdipoR1 and AdipoR2, in bone-forming cells. We show that adiponectin and the receptors are expressed in primary human osteoblasts from femur and tibia. The phenotype of bone cells was confirmed by the high expression levels of alkaline phosphatase, collagen type 1, osteocalcin, and CD44, and the formation of mineralization nodules. Immunostaining with monoclonal antibodies also demonstrated the presence of adiponectin in human osteosarcoma cells and normal osteoblasts. Both mRNA expression and secretion of adiponectin to the medium increased during differentiation of human osteoblasts in culture. The adiponectin mRNA level increases in osteoblasts cultured 3 and 7 days in the presence of dietary fatty acids and supplementation of culture medium with recombinant adiponectin enhances the proliferation of murine osteoblasts. The regulation and detailed function of adiponectin in bone still remains obscure, but our findings suggest a functional role in bone homeostasis. If so, adiponectin may provide an important signal linking fat and body weight to bone density.