Joiner DM, et al. LRP5 and LRP6 in development and disease. Trends Endocrinol Metab. 2013;24(1):31–9.
Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.
Gong Y, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.
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.
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.
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.
Mani A, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007;315(5816):1278–82.
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.
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.
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.
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.
Leupin O, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286(22):19489–500.
Mason JJ, Williams BO. SOST and DKK: antagonists of LRP family signaling as targets for treating bone disease. J Osteoporos. 2010;2010, 460120.
Rey JP, Ellies DL. Wnt modulators in the biotech pipeline. Dev Dyn. 2010;239(1):102–14.
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.
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.
Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–99.
Hogan B. A shared vision. Dev Cell. 2007;13(6):769–71.
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.
Takada S, et al. Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev. 1994;8(2):174–89.
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.
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.
Nagy A. Cre recombinase: the universal reagent for genome tailoring. Genesis. 2000;26(2):99–109.
Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21(1):70–1.
Muzumdar MD, et al. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45(9):593–605.
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.
Zhong ZA, et al. Wntless spatially regulates bone development through beta-catenin-dependent and independent mechanisms. Dev Dyn. 2015;244(10):1347–55.
Holmen SL, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005;280(22):21162–8.
Regard JB, et al. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol. 2012;4(12).
Glass, D.A.2nd, et al., Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005. 8(5): p. 751-764.
Yadav VK, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135(5):825–37.
Kode A, et al. Lrp5 regulation of bone mass and serotonin synthesis in the gut. Nat Med. 2014;20(11):1228–9.
Cui Y, et al. Reply to Lrp5 regulation of bone mass and gut serotonin synthesis. Nat Med. 2014;20(11):1229–30.
Cui Y, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684–91.
Riddle RC, et al. Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. PLoS One. 2013;8(5):e63323.
Shen J, Chen D. Recent progress in osteoarthritis research. J Am Acad Orthop Surg. 2014;22(7):467–8.
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.
Ono N, et al. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014;16(12):1157–67.
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.
Hill TP, et al. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8(5):727–38.
Zhu M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053–64.
Wei W, et al. Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin. Mol Cell Biol. 2011;31(23):4706–19.
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.
Winkler DG, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267–76.
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.
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.
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.
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.
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.
Kakugawa S, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519(7542):187–92.
Brommage R. Genetic Approaches To Identifying Novel Osteoporosis Drug Targets. J Cell Biochem. 2015;116(10):2139–45.
Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262–78.
Zetsche B, et al. Cpf1 Is a single RNA-guided endonuclease of a Class 2 CRISPR-Cas system. Cell. 2015;163(3):759–71.
Baltimore D, et al. Biotechnology. A prudent path forward for genomic engineering and germline gene modification. Science. 2015;348(6230):36–8.
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.
Laine CM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16.
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.
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.
Stark K, et al. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994;372(6507):679–83.
Spater D, et al. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development. 2006;133(15):3039–49.
Yamaguchi TP, et al. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.
Yang Y, et al. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development. 2003;130(5):1003–15.
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.
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.
Bennett CN, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102(9):3324–9.
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.
Zheng HF, et al. WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet. 2012;8(7):e1002745.
Moverare-Skrtic S, et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med. 2014;20(11):1279–88.
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.
Albers J, et al. Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin. J Cell Biol. 2013;200(4):537–49.
Albers J, et al. Control of bone formation by the serpentine receptor Frizzled-9. J Cell Biol. 2011;192(6):1057–72.
Iwaniec UT, et al. PTH stimulates bone formation in mice deficient in Lrp5. J Bone Miner Res. 2007;22(3):394–402.
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.
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.
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.
Pinson KI, et al. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000;407(6803):535–8.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mukhopadhyay M, et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell. 2001;1(3):423–34.
Li X, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet. 2005;37(9):945–52.
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.
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.
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.
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.
Morello R, et al. Brachy-syndactyly caused by loss of Sfrp2 function. J Cell Physiol. 2008;217(1):127–37.
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.
Vasicek TJ, et al. Two dominant mutations in the mouse fused gene are the result of transposon insertions. Genetics. 1997;147(2):777–86.
Dao DY, et al. Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res. 2010;28(1):89–95.
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.
Yu HM, et al. The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development. 2005;132(8):1995–2005.
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.
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.
Hoeflich KP, et al. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406(6791):86–90.
Kugimiya F, et al. GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One. 2007;2(9):e837.
Nelson ER, et al. Role of GSK-3beta in the osteogenic differentiation of palatal mesenchyme. PLoS One. 2011;6(10):e25847.
Joeng KS, et al. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev Biol. 2011;359(2):222–9.
Guo X, et al. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 2004;18(19):2404–17.
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.
Hu H, et al. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132(1):49–60.
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.
Kramer I, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 2010;30(12):3071–85.
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.
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.
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.
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.
Zhu X, et al. Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis. Dev Biol. 2012;365(2):328–38.
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.
Lu C, et al. Wnt-mediated reciprocal regulation between cartilage and bone development during endochondral ossification. Bone. 2013;53(2):566–74.
Akiyama H, et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18(9):1072–87.
Mirando AJ, et al. beta-catenin/cyclin D1 mediated development of suture mesenchyme in calvarial morphogenesis. BMC Dev Biol. 2010;10:116.
Lee HH, Behringer RR. Conditional expression of Wnt4 during chondrogenesis leads to dwarfism in mice. PLoS One. 2007;2(5):e450.
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.
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.
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.
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.
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.
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.
Mikasa M, et al. Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. J Bone Miner Metab. 2011;29(3):291–9.
Hoeppner LH, et al. Lef1DeltaN binds beta-catenin and increases osteoblast activity and trabecular bone mass. J Biol Chem. 2011;286(13):10950–9.