Abstract
A variety of in vivo models have increased understanding of the role of Wnt signaling in bone since mutations in the LRP5 gene were found in human bone disorders. Canonical Wnt signaling encourages mesenchymal progenitor cells to differentiate into osteoblasts. In osteoblasts, Wnt pathway also promotes proliferation and mineralization, while blocks apoptosis and osteoclastogenesis by increasing the OPG/RANKL ratio. Lrp6-mediated signaling in osteoblasts may regulate osteoclastogenesis. However, the role of canonical Wnt signaling in osteoclasts remains unknown, and our understanding of the role of non-canonical Wnt signaling in bone biology is also not sufficient. As to pharmacological intervention, many levels may be considered to target in Wnt signaling pathway, although tumorigenicity and toxicity to other tissues are important. Mesd might be one of target molecules to increase the quantity of LRP5/6 in the plasma membrane. Since sclerostin is almost exclusively expressed in osteocytes, abrogating sclerostin is the most promising design.
Similar content being viewed by others
References
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795
Peacock M, Turner CH, Econs MJ, Foround T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326
Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506
Liu YJ, Shen H, Xiao P, Xiong DH, Li LH, Recker RR, Deng HW (2006) Molecular genetic studies of gene identification for osteoporosis: a 2004 update. J Bone Miner Res 21:1511–1535
Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S 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, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521
Little RD, Carulli JR, Del Mastro RG, Dupuis J, Osborne M 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
Krishnan V, Bryant HU, MacDougald BA (2006) Regulation of bone mass by Wnt signalling. J Clin Invest 116:1202–1209
Baron R, Rawadi G (2007) Targeting the Wnt/β-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635–2643
Glass DA 2nd, Karsenty G (2007) In vivo analysis of Wnt signaling in bone. Endocrinology 148:2630–2634
Balemans W, Van Hul W (2007) The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology 148:2622–2629
Liu F, Kohlmeier S, Wang CY (2008) Wnt signaling and skeletal development. Cell Signal 20:999–1009
He X, Semenov M, Tamai K, Zheg X (2004) LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 131:1663–1677
Kelly OG, Pinson KI, Skarnes WC (2004) The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 131:2803–2815
Huang H, He X (2008) Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 20:119–125
Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines ME, Rosenquist T, Holdener BC (2003) Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 112:355–367
Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810
Moon RT, Kohn AD, De Ferrari GD, Kaykas A (2004) Wnt and β-catenin signalling: diseases and therapies. Nat Rev Genet 5:689–699
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480
Fuerer C, Nusse R, Ten Berge D (2008) Wnt signalling in development and disease. EMBO Rep 9:134–138
Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Bénichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W (2003) Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72:763–771
Koay MA, Brown MA (2005) Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton. Trends Mol Med 11:129–137
Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N et al (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512
van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, GENOMOS Study et al (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290
Kato M, Patel MS, Levasseur R, Lobov I, Chang BHJ, Glass DAII, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (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, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PW, Bhat B, Robinson JA, Marzolf J, Moran RA, Bex F (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974
Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH (2006) The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711
Iwaniec UT, Wronski TJ, Liu J, Rivera MF, Arzaga RR, Hansen G, Brommage R (2007) PTH stimulates bone formation in mice deficient in Lrp5. J Bone Miner Res 22:394–402
Suzuki A, Ozono K, Kubota T, Kondou H, Tachikawa K, Michigami T (2008) PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J Cell Biochem 104:304–317
Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728
Zhang Y, Wang Y, Li X, Zhang J, Mao J, Li Z, Zheng J, Li L, Harris S, Wu D (2004) The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol Cell Biol 24:4677–4684
Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML (2005) Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25:4946–4955
Semenov MV, He X (2006) LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem 281:38276–38284
Ai M, Heeger S, Bartels CF, Schelling DK, Osteoporosis-Pseudoglioma Collaborative Group (2005) Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet 77:741–753
Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407:535–538
Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glant V, Bouxsein ML, Ai M, Warman ML, Williams BO (2004) Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19:2033–2040
Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M, Wahl MB, Galceran J, Grosschedl R, Ozono K, Imai K (2004) Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131:5469–5480
Kubota T, Michigami T, Sakaguchi N, Kokubu C, Suzuki A, Namba N, Sakai N, Nakajima S, Imai K, Ozono K (2008) Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J Bone Miner Res 23(10):1661–1671
Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG (2006) Wnt signaling in osteoblasts regulates expression the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 119:1283–1296
Mani A, Radhakrishnan J, Wang H, Mani A, Mani M-A, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289:950–953
Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60
Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887
Li X, Liu P, Liu W, Maye P, Zhang J, Zhang Y, Hurley M, Guo C, Boskey A, Sun L, Harris SE, Rowe DW, Ke HZ, Wu D (2005) Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37:945–952
Tu X, Joeng KS, Nakayama KI, Nakayama K, Rajagopal J, Carroll TJ, McMahon AP, Long F (2007) Noncanonical Wnt signaling through G protein-linked PKC-delta activation promotes bone formation. Dev Cell 12:113–127
Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329
Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson KD, Macdougald OA (2007) Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem 282:14515–14524
Zhang C, Cho K, Huang Y, Lyons JP, Zhou X, Sinha K, McCrea PD, de Crombrugghe B (2008) Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix. Proc Natl Acad Sci USA 105:6936–6941
Bennett CN, Ouyang H, Ma YL, Zeng Q, Gerin I, Sousa KM, Lane TF, Krishnan V, Hankenson KD, MacDougald OA (2007) Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22:1924–1932
Takada I, Mihara M, Suzawa M, Ohtake F, Kobayashi S, Igarashi M, Youn MY, Takeyama K, Nakamura T, Mezaki Y, Takezawa S, Yogiashi Y, Kitagawa H, Yamada G, Takada S, Minami Y, Shibuya H, Matsumoto K, Kato S (2007) A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol 9:1273–1285
Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, Gaur T, Stein GS, Lian JB, Komm BS (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
Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, Dorward DW, Glinka A, Grinberg A, Huang SP, Niehrs C, Belmonte JC, Westphal H (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1:423–434
Morvan F, Boulukos K, Clément-Lacroix P, Roman Roman S, Suc-Royer I, Vayssière B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (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
Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu Ke H, Li X, Richards WG (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766
Wang FS, Ko JY, Lin CL, Wu HL, Ke HJ, Tai PJ (2007) Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Bone 40:485–492
Chen L, Wang K, Shao Y, Huang J, Li X, Shan J, Wu D, Zheng JJ (2008) Structural insight into the mechanisms of Wnt signaling antagonism by Dkk. J Biol Chem 283:23364–23370
Semënov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775
Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (2006) Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res 21:1738–1749
Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543
Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589
Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97
Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869
Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844
Noble BS (2008) The osteocyte lineage. Arch Biochem Biophys 473:106–111
Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615
Padhi D, Stouch B, Jang G, Fang L, Darling M, Glise H, Robinson M, Harris S, Posvar E (2007) Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women. J Bone Miner Res 22:S37
Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583
Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158
Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957–1967
Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875
O’Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, Robling AG, Bouxsein M, Schipani E, Turner CH, Jilka RL, Weinstein RS, Manolagas SC, Bellido T (2008) Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS ONE 3:e2942
Ali A, Hoeflich KP, Woodgett JR (2001) Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev 101:2527–2540
Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, Warman ML, Baron R, Rawadi G (2005) Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci USA 102:17406–17411
Kulkarni NH, Onyia JE, Zeng Q, Tian X, Liu M, Halladay DL, Frolik CA, Engler T, Wei T, Kriauciunas A, Martin TJ, Sato M, Bryant HU, Ma YL (2006) Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J Bone Miner Res 21:910–920
Vestergaard P, Rejnmark L, Mosekilde L (2007) Fracture risk associated with parkinsonism and anti-Parkinson drugs. Calcif Tissue Int 81:153–161
Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H, Azuma Y, Woodgett JR, Nakamura K, Chung UI (2007) GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS ONE 2:e837
Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750
Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738
Glass DAII, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764
Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere M-C, Bouxsein ML, Deng L, Clemens TL, Williams BO (2005) Essential role of β-catenin in postnatal bone acquisition. J Biol Chem 280:21162–21168
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 280:33132–33140
Acknowledgments
This work was supported in part by Grants-in-Aid from the Research Society for Metabolic Bone Diseases (to K.O.).
Author information
Authors and Affiliations
Corresponding author
Additional information
T. Kubota is a recipient of JSBMR Encouragement Award of 2006.
About this article
Cite this article
Kubota, T., Michigami, T. & Ozono, K. Wnt signaling in bone metabolism. J Bone Miner Metab 27, 265–271 (2009). https://doi.org/10.1007/s00774-009-0064-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-009-0064-8