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Using Genetically Engineered Mouse Models to Study Wnt Signaling in Bone Development and Disease

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Regulation of Signal Transduction in Human Cell Research

Part of the book series: Current Human Cell Research and Applications ((CHCRA))

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Abstract

The skeleton supports the body structure and reserves calcium and other inorganic ions, and more roles played by bone are being proposed. The balance between bone formation (by osteoblasts and osteocytes) and bone resorption (by osteoclasts) controls postnatal bone homeostasis. For the past decade, a vast amount of evidence has shown that Wnt signaling plays a pivotal role in regulating this balance. Therefore, understanding how the Wnt signaling pathway regulates skeletal development and postnatal homeostasis is of great value for human skeletal health. We will review how genetically engineered mouse models (GEMMs) have been and are being used to uncover the mechanisms and etiology of bone diseases in the context of Wnt signaling.

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Abbreviations

CKO:

Conditional knockout

Fzd:

Frizzled

GEMMs:

Genetically engineered mouse models

GOF:

Gain of function

KO:

Full-body knockout

Lrp:

Low-density lipoprotein-related receptor protein

LBM:

Low bone mass

LEF:

Lymphoid enhancer factor

LOF:

Loss of function

MSC:

Mesenchymal stem cell

M-CSF:

Macrophage colony-stimulating factor

NA:

Not applicable

OE:

Overexpression

OMIM:

Online Mendelian Inheritance in Man catalog

OPG:

Osteoprotegerin

RANKL:

Receptor activator of nuclear factor kappa-B ligand

TCF:

T-cell factor

References

  1. Joiner DM, et al. LRP5 and LRP6 in development and disease. Trends Endocrinol Metab. 2013;24(1):31–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.

    Article  CAS  PubMed  Google Scholar 

  3. Gong Y, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.

    Article  CAS  PubMed  Google Scholar 

  4. Little RD, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11–9.

    Article  CAS  PubMed  Google Scholar 

  5. Boyden LM, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513–21.

    Article  CAS  PubMed  Google Scholar 

  6. Van Wesenbeeck L, et al. 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. 2003;72(3):763–71.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mani A, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007;315(5816):1278–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Balemans W, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10(5):537–43.

    Article  CAS  PubMed  Google Scholar 

  9. van Bezooijen RL, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199(6):805–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Johnson EB, Hammer RE, Herz J. Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet. 2005;14(22):3523–38.

    Article  CAS  PubMed  Google Scholar 

  11. Xiong L, et al. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proc Natl Acad Sci U S A. 2015;112(11):3487–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Leupin O, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286(22):19489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mason JJ, Williams BO. SOST and DKK: antagonists of LRP family signaling as targets for treating bone disease. J Osteoporos. 2010;2010, 460120.

    Google Scholar 

  14. Rey JP, Ellies DL. Wnt modulators in the biotech pipeline. Dev Dyn. 2010;239(1):102–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Padhi D, et al. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19–26.

    Article  CAS  PubMed  Google Scholar 

  16. McColm J, et al. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res. 2014;29(4):935–43.

    Article  CAS  PubMed  Google Scholar 

  17. Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hogan B. A shared vision. Dev Cell. 2007;13(6):769–71.

    Article  CAS  PubMed  Google Scholar 

  19. Thomas KR, Capecchi MR. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature. 1990;346(6287):847–50.

    Article  CAS  PubMed  Google Scholar 

  20. Takada S, et al. Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev. 1994;8(2):174–89.

    Article  CAS  PubMed  Google Scholar 

  21. Parr BA, McMahon AP. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature. 1995;374(6520):350–3.

    Article  CAS  PubMed  Google Scholar 

  22. Hamilton DL, Abremski K. Site-specific recombination by the bacteriophage P1 lox-Cre system. Cre-mediated synapsis of two lox sites. J Mol Biol. 1984;178(2):481–6.

    Article  CAS  PubMed  Google Scholar 

  23. Nagy A. Cre recombinase: the universal reagent for genome tailoring. Genesis. 2000;26(2):99–109.

    Article  CAS  PubMed  Google Scholar 

  24. Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21(1):70–1.

    Article  CAS  PubMed  Google Scholar 

  25. Muzumdar MD, et al. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45(9):593–605.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang M, et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002;277(46):44005–12.

    Article  CAS  PubMed  Google Scholar 

  27. Zhong ZA, et al. Wntless spatially regulates bone development through beta-catenin-dependent and independent mechanisms. Dev Dyn. 2015;244(10):1347–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Holmen SL, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005;280(22):21162–8.

    Article  CAS  PubMed  Google Scholar 

  29. Regard JB, et al. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol. 2012;4(12).

    Google Scholar 

  30. Glass, D.A.2nd, et al., Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005. 8(5): p. 751-764.

    Article  CAS  PubMed  Google Scholar 

  31. Yadav VK, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135(5):825–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kode A, et al. Lrp5 regulation of bone mass and serotonin synthesis in the gut. Nat Med. 2014;20(11):1228–9.

    Article  CAS  PubMed  Google Scholar 

  33. Cui Y, et al. Reply to Lrp5 regulation of bone mass and gut serotonin synthesis. Nat Med. 2014;20(11):1229–30.

    Article  CAS  PubMed  Google Scholar 

  34. Cui Y, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Riddle RC, et al. Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. PLoS One. 2013;8(5):e63323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shen J, Chen D. Recent progress in osteoarthritis research. J Am Acad Orthop Surg. 2014;22(7):467–8.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhu M, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009;24(1):12–21.

    Article  CAS  PubMed  Google Scholar 

  38. Ono N, et al. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014;16(12):1157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Day TF, et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739–50.

    Article  CAS  PubMed  Google Scholar 

  40. Hill TP, et al. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8(5):727–38.

    Article  CAS  PubMed  Google Scholar 

  41. Zhu M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wei W, et al. Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin. Mol Cell Biol. 2011;31(23):4706–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Weivoda MM, et al. Wnt Signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways. J Bone Miner Res. 2016;31(1):65–75.

    Article  CAS  PubMed  Google Scholar 

  44. Winkler DG, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brunkow ME, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Maretto S, et al. Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci U S A. 2003;100(6):3299–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhong Z, et al. Wntless functions in mature osteoblasts to regulate bone mass. Proc Natl Acad Sci U S A. 2012;109(33):E2197–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bassett JH, et al. Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength. PLoS Genet. 2012;8(8):e1002858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang X, et al. Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation. Dev Cell. 2015;32(6):719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kakugawa S, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519(7542):187–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brommage R. Genetic Approaches To Identifying Novel Osteoporosis Drug Targets. J Cell Biochem. 2015;116(10):2139–45.

    Article  CAS  PubMed  Google Scholar 

  52. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zetsche B, et al. Cpf1 Is a single RNA-guided endonuclease of a Class 2 CRISPR-Cas system. Cell. 2015;163(3):759–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Baltimore D, et al. Biotechnology. A prudent path forward for genomic engineering and germline gene modification. Science. 2015;348(6230):36–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Joeng KS, et al. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet. 2014;23(15):4035–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Laine CM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Takada I, et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007;9(11):1273–85.

    Article  CAS  PubMed  Google Scholar 

  58. Greco TL, et al. Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev. 1996;10(3):313–24.

    Article  CAS  PubMed  Google Scholar 

  59. Stark K, et al. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994;372(6507):679–83.

    Article  CAS  PubMed  Google Scholar 

  60. Spater D, et al. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development. 2006;133(15):3039–49.

    Article  PubMed  CAS  Google Scholar 

  61. Yamaguchi TP, et al. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.

    CAS  PubMed  Google Scholar 

  62. Yang Y, et al. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development. 2003;130(5):1003–15.

    Article  CAS  PubMed  Google Scholar 

  63. Parr BA, et al. The classical mouse mutant postaxial hemimelia results from a mutation in the Wnt 7a gene. Dev Biol. 1998;202(2):228–34.

    Article  CAS  PubMed  Google Scholar 

  64. Juriloff DM, et al. Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test. Birth Defects Res A Clin Mol Teratol. 2006;76(8):574–9.

    Article  CAS  PubMed  Google Scholar 

  65. Bennett CN, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102(9):3324–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stevens JR, et al. Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J Bone Miner Res. 2010;25(10):2138–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zheng HF, et al. WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet. 2012;8(7):e1002745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Moverare-Skrtic S, et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med. 2014;20(11):1279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu H, et al. Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes. Development. 2010;137(21):3707–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Albers J, et al. Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin. J Cell Biol. 2013;200(4):537–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Albers J, et al. Control of bone formation by the serpentine receptor Frizzled-9. J Cell Biol. 2011;192(6):1057–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Iwaniec UT, et al. PTH stimulates bone formation in mice deficient in Lrp5. J Bone Miner Res. 2007;22(3):394–402.

    Article  CAS  PubMed  Google Scholar 

  73. Clement-Lacroix P, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005;102(48):17406–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kato M, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157(2):303–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Holmen SL, et al. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res. 2004;19(12):2033–40.

    Article  CAS  PubMed  Google Scholar 

  76. Pinson KI, et al. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000;407(6803):535–8.

    Article  CAS  PubMed  Google Scholar 

  77. Carter M, et al. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Proc Natl Acad Sci U S A. 2005;102(36):12843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kokubu C, et al. Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development. 2004;131(21):5469–80.

    Article  CAS  PubMed  Google Scholar 

  79. Kubota T, et al. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J Bone Miner Res. 2008;23(10):1661–71.

    Article  CAS  PubMed  Google Scholar 

  80. Karner CM, et al. Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome. PLoS One. 2010;5(4):e10418.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Simon-Chazottes D, et al. Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse. Genomics. 2006;87(5):673–7.

    Article  CAS  PubMed  Google Scholar 

  82. Weatherbee SD, Anderson KV, Niswander LA. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development. 2006;133(24):4993–5000.

    Article  CAS  PubMed  Google Scholar 

  83. Choi HY, et al. Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS One. 2009;4(11):e7930.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Fu J, et al. Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci U S A. 2009;106(44):18598–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Morvan F, et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res. 2006;21(6):934–45.

    Article  CAS  PubMed  Google Scholar 

  86. Mukhopadhyay M, et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell. 2001;1(3):423–34.

    Article  CAS  PubMed  Google Scholar 

  87. Li X, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet. 2005;37(9):945–52.

    Article  CAS  PubMed  Google Scholar 

  88. Li C, et al. Increased callus mass and enhanced strength during fracture healing in mice lacking the sclerostin gene. Bone. 2011;49(6):1178–85.

    Article  CAS  PubMed  Google Scholar 

  89. Li X, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860–9.

    Article  PubMed  Google Scholar 

  90. Niziolek PJ, et al. High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. Bone. 2011;49(5):1010–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bodine PV, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol. 2004;18(5):1222–37.

    Article  CAS  PubMed  Google Scholar 

  92. Morello R, et al. Brachy-syndactyly caused by loss of Sfrp2 function. J Cell Physiol. 2008;217(1):127–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Perry WL 3rd, et al. Phenotypic and molecular analysis of a transgenic insertional allele of the mouse Fused locus. Genetics. 1995;141(1):321–32.

    CAS  PubMed  Google Scholar 

  94. Vasicek TJ, et al. Two dominant mutations in the mouse fused gene are the result of transposon insertions. Genetics. 1997;147(2):777–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Dao DY, et al. Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res. 2010;28(1):89–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yan Y, et al. Axin2 controls bone remodeling through the beta-catenin-BMP signaling pathway in adult mice. J Cell Sci. 2009;122(Pt 19):3566–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yu HM, et al. The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development. 2005;132(8):1995–2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Qian L, et al. Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo. Proc Natl Acad Sci U S A. 2011;108(21):8692–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Itoh S, et al. GSK-3alpha and GSK-3beta proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation. J Biol Chem. 2012;287(35):29227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hoeflich KP, et al. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406(6791):86–90.

    Article  CAS  PubMed  Google Scholar 

  101. Kugimiya F, et al. GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One. 2007;2(9):e837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Nelson ER, et al. Role of GSK-3beta in the osteogenic differentiation of palatal mesenchyme. PLoS One. 2011;6(10):e25847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Joeng KS, et al. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev Biol. 2011;359(2):222–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guo X, et al. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 2004;18(19):2404–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Soshnikova N, et al. Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev. 2003;17(16):1963–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hu H, et al. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132(1):49–60.

    Article  CAS  PubMed  Google Scholar 

  107. Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006;133(16):3231–44.

    Article  CAS  PubMed  Google Scholar 

  108. Kramer I, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 2010;30(12):3071–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dao DY, et al. Cartilage-specific beta-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Miner Res. 2012;27(8):1680–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chen J, Long F. β-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice. J Bone Miner Res. 2013;8(5):1160–9.

    Article  CAS  Google Scholar 

  111. Barrott JJ, et al. Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome. Proc Natl Acad Sci U S A. 2011;108(31):12752–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu W, et al. Deletion of Porcn in mice leads to multiple developmental defects and models human focal dermal hypoplasia (Goltz syndrome). PLoS One. 2012;7(3):e32331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhu X, et al. Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis. Dev Biol. 2012;365(2):328–38.

    Article  CAS  PubMed  Google Scholar 

  114. Maruyama T, Jiang M, Hsu W. Gpr177, a novel locus for bone-mineral-density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development. J Bone Miner Res. 2013;28(5):1150–9.

    Google Scholar 

  115. Lu C, et al. Wnt-mediated reciprocal regulation between cartilage and bone development during endochondral ossification. Bone. 2013;53(2):566–74.

    Article  CAS  PubMed  Google Scholar 

  116. Akiyama H, et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18(9):1072–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mirando AJ, et al. beta-catenin/cyclin D1 mediated development of suture mesenchyme in calvarial morphogenesis. BMC Dev Biol. 2010;10:116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Lee HH, Behringer RR. Conditional expression of Wnt4 during chondrogenesis leads to dwarfism in mice. PLoS One. 2007;2(5):e450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Popperl H, et al. Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development. 1997;124(15):2997–3005.

    CAS  PubMed  Google Scholar 

  120. Oh H, Chun CH, Chun JS. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2012;64(8):2568–78.

    Article  CAS  PubMed  Google Scholar 

  121. Oh H, et al. Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification. J Bone Miner Res. 2012;27(6):1335–44.

    Article  CAS  PubMed  Google Scholar 

  122. Yao GQ, et al. Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in mice. J Bone Miner Metab. 2011;29(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  123. Cho HY, et al. Transgenic mice overexpressing secreted frizzled-related proteins (sFRP)4 under the control of serum amyloid P promoter exhibit low bone mass but did not result in disturbed phosphate homeostasis. Bone. 2010;47(2):263–71.

    Article  CAS  PubMed  Google Scholar 

  124. Nakanishi R, et al. Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res. 2008;23(2):271–7.

    Article  CAS  PubMed  Google Scholar 

  125. Mikasa M, et al. Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. J Bone Miner Metab. 2011;29(3):291–9.

    Article  CAS  PubMed  Google Scholar 

  126. Hoeppner LH, et al. Lef1DeltaN binds beta-catenin and increases osteoblast activity and trabecular bone mass. J Biol Chem. 2011;286(13):10950–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA

    Zhendong A. Zhong, Nicole J. Ethen & Bart O. Williams

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  1. Zhendong A. Zhong
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  2. Nicole J. Ethen
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  3. Bart O. Williams
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Correspondence to Bart O. Williams .

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  1. Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan

    Nariyoshi Shinomiya

  2. Department of Pathology, University of Miyazaki, Miyazaki, Miyazaki, Japan

    Hiroaki Kataoka

  3. Department of Biomedical Sciences, Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson, Tennessee, USA

    Qian Xie

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Zhong, Z.A., Ethen, N.J., Williams, B.O. (2018). Using Genetically Engineered Mouse Models to Study Wnt Signaling in Bone Development and Disease. In: Shinomiya, N., Kataoka, H., Xie, Q. (eds) Regulation of Signal Transduction in Human Cell Research. Current Human Cell Research and Applications. Springer, Singapore. https://doi.org/10.1007/978-981-10-7296-3_1

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  • DOI: https://doi.org/10.1007/978-981-10-7296-3_1

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