The Anti-Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5

Oxford University Press (OUP) - Tập 30 Số 7 - Trang 1175-1183 - 2015
Timur Yorgan1, Stephanie Peters1, Anke Jeschke1, Peggy Benisch2, Franz Jakob2, Michael Amling1, Thorsten Schinke1
1Department of Osteology & Biomechanics; University Medical Center Hamburg-Eppendorf; Hamburg Germany
2Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany

Tóm tắt

ABSTRACT   Activating mutations of the putative Wnt co-receptor Lrp5 or inactivating mutations of the secreted molecule Sclerostin cause excessive bone formation in mice and humans. Previous studies have suggested that Sclerostin functions as an Lrp5 antagonist, yet clear in vivo evidence was still missing, and alternative mechanisms have been discussed. Moreover, because osteoblast-specific inactivation of β-catenin, the major intracellular mediator of canonical Wnt signaling, primarily affected bone resorption, it remained questionable, whether Sclerostin truly acts as a Wnt signaling antagonist by interacting with Lrp5. In an attempt to address this relevant question, we generated a mouse model (Col1a1-Sost) with transgenic overexpression of Sclerostin under the control of a 2.3-kb Col1a1 promoter fragment. These mice displayed the expected low bone mass phenotype as a consequence of reduced bone formation. The Col1a1-Sost mice were then crossed with two mouse lines carrying different high bone mass mutations of Lrp5 (Lrp5A170V and Lrp5G213V), both of them potentially interfering with Sclerostin binding. Using µCT-scanning and histomorphometry we found that the anti-osteoanabolic influence of Sclerostin overexpression was not observed in Lrp5A213V/A213V mice and strongly reduced in Lrp5A170V/A170V mice. As a control we applied the same strategy with mice overexpressing the transmembrane Wnt signaling antagonist Krm2 and found that the anti-osteoanabolic influence of the Col1a1-Krm2 transgene was not affected by either of the Lrp5 mutations. Taken together, our data support the concept that Sclerostin inhibits bone formation through Lrp5 interaction, yet their physiological relevance remains to be established. © 2015 American Society for Bone and Mineral Research.

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Tài liệu tham khảo

Saito-Diaz, 2013, The way Wnt works: components and mechanism, Growth Factors., 31, 1, 10.3109/08977194.2012.752737

Baron, 2013, WNT signaling in bone homeostasis and disease: from human mutations to treatments, Nat Med., 19, 179, 10.1038/nm.3074

Clevers, 2012, Wnt/beta-catenin signaling and disease, Cell., 149, 1192, 10.1016/j.cell.2012.05.012

Tamai, 2000, LDL-receptor-related proteins in Wnt signal transduction, Nature., 407, 530, 10.1038/35035117

Pinson, 2000, An LDL-receptor-related protein mediates Wnt signalling in mice, Nature., 407, 535, 10.1038/35035124

Boyden, 2002, High bone density due to a mutation in LDL-receptor-related protein 5, N Engl J Med., 346, 1513, 10.1056/NEJMoa013444

Gong, 2001, LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development, Cell., 107, 513, 10.1016/S0092-8674(01)00571-2

Little, 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, 10.1086/338450

Kato, 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, 10.1083/jcb.200201089

Babij, 2003, High bone mass in mice expressing a mutant LRP5 gene, J Bone Miner Res., 18, 960, 10.1359/jbmr.2003.18.6.960

Cui, 2011, Lrp5 functions in bone to regulate bone mass, Nat Med., 17, 684, 10.1038/nm.2388

Glass, 2005, Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation, Dev Cell., 8, 751, 10.1016/j.devcel.2005.02.017

Holmen, 2005, Essential role of beta-catenin in postnatal bone acquisition, J Biol Chem., 280, 21162, 10.1074/jbc.M501900200

Kramer, 2010, Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis, Mol Cell Biol., 30, 3071, 10.1128/MCB.01428-09

Ai, 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, 10.1128/MCB.25.12.4946-4955.2005

Morvan, 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, 10.1359/jbmr.060311

Li, 2006, Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia, Bone., 39, 754, 10.1016/j.bone.2006.03.017

Mao, 2002, Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling, Nature., 417, 664, 10.1038/nature756

Schulze, 2010, Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2, PLoS One., 5, e10309, 10.1371/journal.pone.0010309

Weivoda, 2014, Developments in sclerostin biology: regulation of gene expression, mechanisms of action, and physiological functions, Curr Osteoporos Rep., 12, 107, 10.1007/s11914-014-0188-1

Lewiecki, 2014, Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases, Ther Adv Musculoskelet Dis., 6, 48, 10.1177/1759720X13510479

Balemans, 2001, Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST), Hum Mol Genet., 10, 537, 10.1093/hmg/10.5.537

Balemans, 2002, Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease, J Med Genet., 39, 91, 10.1136/jmg.39.2.91

Nolan, 2014, The DAN family: modulators of TGF-β signaling and beyond, Protein Sci., 23, 999, 10.1002/pro.2485

Li, 2005, Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling, J Biol Chem., 280, 19883, 10.1074/jbc.M413274200

Semenov, 2005, SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor, J Biol Chem., 280, 26770, 10.1074/jbc.M504308200

Ellies, 2006, Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity, J Bone Miner Res., 21, 1738, 10.1359/jbmr.060810

Semenov, 2006, LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST, J Biol Chem., 281, 38276, 10.1074/jbc.M609509200

Balemans, 2008, The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations, Calcif Tissue Int., 82, 445, 10.1007/s00223-008-9130-9

Kedlaya, 2013, Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome, Sci Transl Med., 5, 211ra158, 10.1126/scitranslmed.3006627

Chang, 2014, Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity, J Bone Miner Res., 29, 29, 10.1002/jbmr.2059

Choi, 2009, Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo, PLoS One., 4, e7930, 10.1371/journal.pone.0007930

Leupin, 2011, Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function, J Biol Chem., 286, 19489, 10.1074/jbc.M110.190330

Winkler, 2003, Osteocyte control of bone formation via sclerostin, a novel BMP antagonist, EMBO J., 22, 6267, 10.1093/emboj/cdg599

Kusu, 2003, Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity, J Biol Chem., 278, 24113, 10.1074/jbc.M301716200

Niziolek, 2011, High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes, Bone., 49, 1010, 10.1016/j.bone.2011.07.034

Niziolek, 2012, Mechanotransduction in bone tissue: The A214V and G171V mutations in Lrp5 enhance load-induced osteogenesis in a surface-selective manner, Bone., 51, 459, 10.1016/j.bone.2012.05.023

Rossert, 1995, Separate cis-acting DNA elements of the mouse pro-alpha 1(I) collagen promoter direct expression of reporter genes to different type I collagen-producing cells in transgenic mice, J Cell Biol., 129, 1421, 10.1083/jcb.129.5.1421

Albers, 2013, Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin, J Cell Biol., 200, 537, 10.1083/jcb.201207142

Parfitt, 1987, Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee, J Bone Miner Res., 2, 595, 10.1002/jbmr.5650020617

Schulze, 2011, Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells, J Bone Miner Res., 26, 704, 10.1002/jbmr.269

Doube, 2010, BoneJ: free and extensible bone image analysis in ImageJ, Bone., 47, 1076, 10.1016/j.bone.2010.08.023

Schindelin, 2012, Fiji: an open-source platform for biological-image analysis, Nat Methods., 9, 676, 10.1038/nmeth.2019

Dacquin, 2002, Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast, Dev Dyn., 224, 245, 10.1002/dvdy.10100

Li, 2008, Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength, J Bone Miner Res., 23, 860, 10.1359/jbmr.080216

Rhee, 2011, PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling, J Bone Miner Res., 26, 1035, 10.1002/jbmr.304

Jho, 2002, Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway, Mol Cell Biol., 22, 1172, 10.1128/MCB.22.4.1172-1183.2002

Jukkola, 2004, Drapc1 expression during mouse embryonic development, Gene Expr Patterns., 4, 755, 10.1016/j.modgep.2004.03.006

Yadav, 2008, Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum, Cell., 135, 825, 10.1016/j.cell.2008.09.059

Kode, 2014, Lrp5 regulation of bone mass and serotonin synthesis in the gut, Nat Med., 20, 1228, 10.1038/nm.3698

Cui, 2014, Reply to Lrp5 regulation of bone mass and gut serotonin synthesis, Nat Med., 20, 1229, 10.1038/nm.3697

McClung, 2014, Romosozumab in postmenopausal women with low bone mineral density, N Engl J Med., 370, 412, 10.1056/NEJMoa1305224

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Oxford University Press (OUP)

Tập 30 Số 7

1175-1183

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