Luther J, et al. - Given the association of WNT1 mutations in humans with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation, researchers aimed to establish the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging. Heterozygous WNT1 mutations were highly prevalent in patients with early-onset osteoporosis. Severe osteoporosis and spontaneous bone fractures in mice were noted on inactivating Wnt1 in osteoblasts. In contrast to current mechanistic models, no reduced bone-anabolic effect of Wnt1 was evident with loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation. This suggests that Wnt1 function does not require the LRP5 co-receptor. Findings thus indicate that Wnt1 is a regulator of bone formation and remodeling. This provides the basis for the development of Wnt1-targeting drugs for the treatment of osteoporosis.