Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling

PLoS ONE

Volumn 8, Issue 4, 2013, Pages

  van Dinther, Maarten ^a   Zhang, Juan ^a   Weidauer, Stella E ^b   Boschert, Verena ^b   Muth, Eva Maria ^b   Knappik, Achim ^c   de Gorter, David J J ^a   van Kasteren, Puck B ^a   Frisch, Christian ^c   Mueller, Thomas D ^b   ten Dijke, Peter ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF WÜRZBURG   (Germany)

^c Division of MorphoSys   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALKALINE PHOSPHATASE; CELL SURFACE PROTEIN; CLATHRIN; DICKKOPF 1 PROTEIN; FLUORESCENT DYE; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 5; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 6; MESSENGER RNA; PROTEASOME; PROTEIN ANTIBODY; RECOMBINANT GREEN FLUORESCENT PROTEIN; SCLEROSTIN; SCLEROSTIN ANTIBODY; SERINE; UNCLASSIFIED DRUG; WNT PROTEIN; WNT3A PROTEIN; GLYCOPROTEIN; LRP5 PROTEIN, MOUSE; LRP6 PROTEIN, MOUSE; NEUTRALIZING ANTIBODY; SOST PROTEIN, MOUSE;

AFFINITY LABELING; ANIMAL CELL; ARTICLE; CELL DIFFERENTIATION; CELL TRANSPORT; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME INDUCTION; GENE EXPRESSION; GENE SILENCING; INHIBITION KINETICS; INTERNALIZATION; MESENCHYME CELL; MOUSE; NONHUMAN; OSTEOBLAST; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TEMPERATURE SENSITIVITY; TRANSCRIPTION REGULATION; ANIMAL; ANTIBODY SPECIFICITY; CELL LINE; CYTOLOGY; HUMAN; IMMUNOLOGY; METABOLISM; PHOSPHORYLATION; PROTEIN TRANSPORT;

ANIMALS; ANTIBODIES, NEUTRALIZING; ANTIBODY SPECIFICITY; CELL DIFFERENTIATION; CELL LINE; GLYCOPROTEINS; HUMANS; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-6; MICE; OSTEOBLASTS; PHOSPHORYLATION; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; WNT PROTEINS;

EID: 84876914764     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0062295     Document Type: Article

References (57)

1. Olson BR (2006) Bone embryology. In: Favus MJ, editor. Primer on the Metabolic Bone Diseases And Disorders of Mineral Metabolism. Washington DC: American society for bone and mineral research. 2-6.
2. Marie PJ, (2012) Signaling pathways affecting skeletal health. Current osteoporosis reports 10: 190-198.
3. Rachner TD, Khosla S, Hofbauer LC, (2011) Osteoporosis: now and the future. Lancet 377: 1276-1287.
4. Kawai M, Mödder UI, Khosla S, Rosen CJ, (2011) Emerging therapeutic opportunities for skeletal restoration. Nature reviews Drug discovery 10: 141-156.
5. Baron R, Hesse E, (2012) Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. The Journal of clinical endocrinology and metabolism 97: 311-325.
6. Janssens K, Van Hul W, (2002) Molecular genetics of too much bone. Human molecular genetics 11: 2385-2393.
7. Kaplan FS, Pignolo RJ, Shore EM (n.d.) The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. Cytokine & growth factor reviews 20: 399-407.
8. Lewiecki EM, (2011) New targets for intervention in the treatment of postmenopausal osteoporosis. Nature reviews Rheumatology 7: 631-638.
9. Balemans W, Van Hul W, (2004) Identification of the disease-causing gene in sclerosteosis-discovery of a novel bone anabolic target? Journal of musculoskeletal & neuronal interactions 4: 139-142.
10. van Bezooijen RL, ten Dijke P, Papapoulos SE, Löwik CWGM, (2005) SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine & growth factor reviews 16: 319-327.
11. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, et al. (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Human molecular genetics 10: 537-543.
12. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, et al. (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. American journal of human genetics 68: 577-589.
13. Li X, Ominsky MS, Niu Q-T, Sun N, Daugherty B, et al. (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 23: 860-869.
14. Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJJ, et al. (2010) Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. The Journal of biological chemistry 285: 41614-41626.
15. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, et al. (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. The EMBO journal 22: 6267-6276.
16. Li X, Zhang Y, Kang H, Liu W, Liu P, et al. (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. The Journal of biological chemistry 280: 19883-19887.
17. Semënov M, Tamai K, He X, (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. The Journal of biological chemistry 280: 26770-26775.
18. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, et al. (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 22: 19-28.
19. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, et al. (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407: 530-535.
20. 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.
21. Ettenberg SA, Charlat O, Daley MP, Liu S, Vincent KJ, et al. (2010) Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proceedings of the National Academy of Sciences of the United States of America 107: 15473-15478.
22. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, et al. (2002) High bone density due to a mutation in LDL-receptor-related protein 5. The New England journal of medicine 346: 1513-1521.
23. Little RD, Carulli JP, 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. American journal of human genetics 70: 11-19.
24. Ellies DL, Viviano B, McCarthy J, Rey J-P, Itasaki N, et al. (2006) Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 21: 1738-1749.
25. Leupin O, Piters E, Halleux C, Hu S, Kramer I, et al. (2011) Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. The Journal of biological chemistry 286: 19489-19500.
26. Jho E, Zhang T, Domon C, Joo C-K, Freund J-N, et al. (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Molecular and cellular biology 22: 1172-1183.
27. Mao B, Wu W, Davidson G, Marhold J, Li M, et al. (2002) Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417: 664-667.
28. Brott BK, Sokol SY, (2002) Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Molecular and cellular biology 22: 6100-6110.
29. Bourhis E, Tam C, Franke Y, Bazan JF, Ernst J, et al. (2010) Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6. The Journal of biological chemistry 285: 9172-9179.
30. Mao B, Wu W, Li Y, Hoppe D, Stannek P, et al. (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321-325.
31. Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, et al. (2001) Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Current biology: CB 11: 951-961.
32. Zhang J, Zhang X, Zhang L, Zhou F, van Dinther M, et al. (2012) LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 27: 2065-2074.
33. Niehrs C, Shen J, (2010) Regulation of Lrp6 phosphorylation. Cellular and molecular life sciences: CMLS 67: 2551-2562.
34. Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, et al. (2009) NMR structure of the Wnt modulator protein Sclerostin. Biochemical and biophysical research communications 380: 160-165.
35. Yamamoto H, Sakane H, Michiue T, Kikuchi A (2008) Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling.
36. Schlegel R, Dickson RB, Willingham MC, Pastan IH, (1982) Amantadine and dansylcadaverine inhibit vesicular stomatitis virus uptake and receptor-mediated endocytosis of alpha 2-macroglobulin. Proceedings of the National Academy of Sciences of the United States of America 79: 2291-2295.
37. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, et al. (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68: 673-682.
38. Rothe C, Urlinger S, Löhning C, Prassler J, Stark Y, et al. (2008) The human combinatorial antibody library HuCAL GOLD combines diversification of all six CDRs according to the natural immune system with a novel display method for efficient selection of high-affinity antibodies. Journal of molecular biology 376: 1182-1200.
39. Ostendorp R, Frisch C, Urban M (2004) Generation, engineering and production of human antibodies using HuCAL. In: Subramanian G, editor. Antibodies Volume 2: Novel Technologies and Therapeutic Use. New York: Kluwer Academic/Plenum Publishers. 13-52.
40. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, et al. (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 24: 578-588.
41. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, et al. (2010) Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 25: 948-959.
42. Ominsky MS, Li C, Li X, Tan HL, Lee E, et al. (2011) Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 26: 1012-1021.
43. Padhi D, Jang G, Stouch B, Fang L, Posvar E, (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 26: 19-26.
44. Virdi AS, Liu M, Sena K, Maletich J, McNulty M, et al. (2012) Sclerostin antibody increases bone volume and enhances implant fixation in a rat model. The Journal of bone and joint surgery American volume 94: 1670-1680.
45. McDonald MM, Morse A, Mikulec K, Peacock L, Yu N, et al. (2012) Inhibition of sclerostin by systemic treatment with sclerostin antibody enhances healing of proximal tibial defects in ovariectomized rats. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 30: 1541-1548.
46. Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA, (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nature cell biology 3: 683-686.
47. Sakane H, Yamamoto H, Kikuchi A (2010) LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse. Journal of cell science 123: 360-.
48. Ahn VE, Chu ML-H, Choi H-J, Tran D, Abo A, et al. (2011) Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Developmental cell 21: 862-873.
49. Cheng Z, Biechele T, Wei Z, Morrone S, Moon RT, et al. (2011) Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nature structural & molecular biology 18: 1204-1210.
50. Bourhis E, Wang W, Tam C, Hwang J, Zhang Y, et al. (2011) Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6. Structure (London, England: 1993) 19: 1433-1442.
51. Gong Y, Bourhis E, Chiu C, Stawicki S, DeAlmeida VI, et al. (2010) Wnt isoform-specific interactions with coreceptor specify inhibition or potentiation of signaling by LRP6 antibodies. PloS one 5: e12682.
52. Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, et al. (2009) Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. The Journal of biological chemistry 284: 10890-10900.
53. Yamashita T, Ishii H, Shimoda K, Sampath TK, Katagiri T, et al. (1996) Subcloning of three osteoblastic cell lines with distinct differentiation phenotypes from the mouse osteoblastic cell line KS-4. Bone 19: 429-436.
54. Atsumi T, Miwa Y, Kimata K, Ikawa Y, (1990) A chondrogenic cell line derived from a differentiating culture of AT805 teratocarcinoma cells. Cell differentiation and development: the official journal of the International Society of Developmental Biologists 30: 109-116.
55. Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, et al. (2003) Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proceedings of the National Academy of Sciences of the United States of America 100: 3299-3304.
56. Frolik CA, Wakefield LM, Smith DM, Sporn MB, (1984) Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. The Journal of biological chemistry 259: 10995-11000.
57. Yamashita H, ten Dijke P, Huylebroeck D, Sampath TK, Andries M, et al. (1995) Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. The Journal of cell biology 130: 217-226.