Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand

Julia Luther1,*, Timur Alexander Yorgan1,*, Tim Rolvien1,*, Lorenz Ulsamer1, Till Koehne1,2, Nannan Liao1, Daniela Keller1,†, Nele Vollersen1, Stefan Teufel1,‡, Mona Neven1, Stephanie Peters1, Michaela Schweizer3, Andreas Trumpp4, Sebastian Rosigkeit5, Ernesto Bockamp5, Stefan Mundlos6,7,8, Uwe Kornak6,7,8, Ralf Oheim1, Michael Amling1,§, Thorsten Schinke1,§ and Jean-Pierre David1,§

Science Translational Medicine  07 Nov 2018: Vol. 10, Issue 466, eaau7137 DOI: 10.1126/scitranslmed.aau7137

Building bone

Wnt signaling is important for proper embryonic development, shaping cell fate and migration, stem cell renewal, and organ and tissue formation. Here, Luther et al. investigated the role of Wnt1 in osteoporosis. Patients with early-onset osteoporosis and with WNT1 mutations had low bone turnover and high fracture rates, and loss of Wnt1 activity caused fracture and osteoporosis in mice. Inducing Wnt1 in bone-forming cells increased bone mass in aged mice, and this process did not require Lrp5, a co-receptor involved in Wnt signaling. This study identifies Wnt1 as an anabolic (bone building) factor and suggests that it might be a therapeutic target for osteoporosis.


WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.


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