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Targeting WNT signaling in the treatment of osteoporosis
Abstract
Osteoporosis is a widespread chronic disease characterized by low bone density, altered microstructure and bone fragility, leading to low impact fractures in affected individuals. The discovery of a few mutations that cause extremely rare human diseases has identified the WNT signaling pathway as a candidate for therapeutic intervention aimed at increasing bone mass and strength. In particular, inhibition of sclerostin, a WNT antagonist secreted by osteocytes, has proven in clinical trials to be a very efficient osteo-anabolic approach. One year of monthly administration of antibodies to sclerostin rapidly decreases bone resorption and increases bone formation and bone density at all sites, decreasing markedly fracture risk in treated patients. Their effect is however limited in time and cardiovascular adverse events have been reported in one clinical trial.
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“The activation of the canonical Wnt signaling usually increases, while the inhibition of the pathway decreases bone mass and strength [30].”
From N-myc downstream regulated gene 1 suppresses osteoblast differentiation through inactivating Wnt/β-catenin signaling (2022) · cites this paper as [30]
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Cosman, F., Crittenden, D. B., Adachi, J. D., Binkley, N., Czerwinski, E., Ferrari, S., Hofbauer, L. C., Lau, E., Lewiecki, E. M., Miyauchi, A., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1607948 · Cited by 1,805
High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5
Boyden, L. M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M. A., Wu, D., Insogna, K., & Lifton, R. P. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa013444 · Cited by 1,591
Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis
Saag, K. G., Petersen, J., Brandi, M. L., Karaplis, A. C., Lorentzon, M., Thomas, T., Maddox, J., Fan, M., Meisner, P. D., & Grauer, A. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1708322 · Cited by 1,544
Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling
Li, X., Zhang, Y., Kang, H., Liu, W., Liu, P., Zhang, J., Harris, S. E., & Wu, D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413274200 · Cited by 1,366
Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin
Robling, A. G., Niziolek, P. J., Baldridge, L. A., Condon, K. W., Allen, M. R., Alam, I., Mantila, S. M., Gluhak-Heinrich, J., Bellido, T. M., Harris, S. E., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m705092200 · Cited by 1,350
Romosozumab in Postmenopausal Women with Low Bone Mineral Density
McClung, M. R., Grauer, A., Boonen, S., Bolognese, M. A., Brown, J. P., Diez-Perez, A., Langdahl, B. L., Reginster, J.-Y., Zanchetta, J. R., Wasserman, S. M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1305224 · Cited by 1,258
Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation
Poole, K. E. S., Van Bezooijen, R. L., Loveridge, N., Hamersma, H., Papapoulos, S. E., Löwik, C. W., & Reeve, J. (2005) · The FASEB Journal · doi:10.1096/fj.05-4221fje · Cited by 965
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Metadata
- Authors
- Baron, R., & Gori, F.
- Venue
- Current Opinion in Pharmacology
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 40
- Pages
- 134-141
- ISSN
- 1471-4892
- Cited by
- 101
- References
- 9
- Language
- en
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