Abstract
The Wnt genes encode a highly conserved class of signaling factors required for the development of several types of tissues including musculoskeletal and neural structures. There is increasing evidence that Wnt signaling is critical for bone mass accrual, bone remodeling, and fracture repair. Wnt proteins bind to cell-surface receptors and activate signaling pathways which control nuclear gene expression; this Wnt-regulated gene expression controls cell growth and differentiation. Many of the components of the Wnt pathway have recently been characterized, and specific loss-of-function or gain-of-function mutations in this pathway in mice and in humans have resulted in disorders of deficient or excess bone formation, respectively. Pharmacologically targeting components of the Wnt signaling pathway will allow for the manipulation of bone formation and remodeling and will have several orthopedic applications including enhancing bone formation in nonunion and osteoporosis and restricting pathologic bone formation in osteogenic tumors and heterotopic ossification.
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Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810
Nusse R (2005) Wnt signaling in disease and in development. Cell Res 15:28–32
Nusse R, Varmus HE (1992) Wnt genes. Cell 69:1073–1087
Westendorf JJ, Kahler RA, Schroeder TM (2004) Wnt signaling in osteoblasts and bone diseases. Gene 341:19–39
Baron R, Rawadi G, Roman-Roman S (2006) Wnt signaling: a key regulator of bone mass. Curr Top Dev Biol 76:103–127
Day TF, Guo X, Garrett-Beal L, et al. (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750
Glass DA, 2nd, Bialek P, Ahn JD, et al. (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764
Gregory CA, Gunn WG, Reyes E, et al. (2005) How Wnt signaling affects bone repair by mesenchymal stem cells from the bone marrow. Ann N Y Acad Sci 1049:97–106
Hill TP, Spater D, Taketo MM, et al. (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738
Hu H, Hilton MJ, Tu X, et al. (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60
Rodda SJ, McMahon AP (2006) Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133:3231–3244
Montcouquiol M, Crenshaw EB, 3rd, Kelley MW (2006) Noncanonical Wnt signaling and neural polarity. Annu Rev Neurosci 29:363–386
Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116:2627–2634
Ladher RK, Church VL, Allen S, et al. (2000) Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development. Dev Biol 218:183–198
Glinka A, Wu W, Delius H, et al. (1998) Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391:357–362
Behrens J, Lustig B (2004) The Wnt connection to tumorigenesis. Int J Dev Biol 48:477–487
Nathke IS (2004) The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Annu Rev Cell Dev Biol 20:337–366
Hoang BH, Kubo T, Healey JH, et al. (2004) Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer 109:106–111
Uren A, Wolf V, Sun YF, et al. (2004) Wnt/Frizzled signaling in Ewing sarcoma. Pediatr Blood Cancer 43:243–249
Niemann S, Zhao C, Pascu F, et al. (2004) Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet 74:558–563
Gong Y, Slee RB, Fukai N, et al. (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523
Boyden LM, Mao J, Belsky J, et al. (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521
Little RD, Carulli JP, Del Mastro RG, et al. (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70:11–19
Kato M, Patel MS, Levasseur R, et al. (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314
Babij P, Zhao W, Small C, et al. (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974
Bodine PV, Zhao W, Kharode YP, et al. (2004) The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 18:1222–1237
Holmen SL, Zylstra CR, Mukherjee A, et al. (2005) Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 280:21162–21168
Li J, Sarosi I, Cattley RC, et al. (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766
Morvan F, Boulukos K, Clement-Lacroix P, et al. (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945
Roodman GD (2006) Regulation of osteoclast differentiation. Ann N Y Acad Sci 1068:100–109
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Issack, P.S., Helfet, D.L. & Lane, J.M. Role of Wnt Signaling in Bone Remodeling and Repair. HSS Jrnl 4, 66–70 (2008). https://doi.org/10.1007/s11420-007-9072-1
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DOI: https://doi.org/10.1007/s11420-007-9072-1