Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome

Science Translational Medicine

Volumn 5, Issue 211, 2013, Pages

  Kedlaya, Rajendra ^a   Veera, Shreya ^a   Horan, Daniel J ^a,b   Moss, Rachel E ^a   Ayturk, Ugur M ^c   Jacobsen, Christina M ^c   Bowen, Margot E ^c   Paszty, Chris ^d   Warman, Matthew L ^c,e   Robling, Alexander G ^a,b,f  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b RICHARD L ROUDEBUSH VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c BOSTON CHILDREN S HOSPITAL   (United States)

^d AMGEN INC   (United States)

^e HARVARD MEDICAL SCHOOL   (United States)

^f Indiana University Purdue University Indianapolis   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 5; NEUTRALIZING ANTIBODY; PROTEIN ANTIBODY; SCLEROSTIN; SCLEROSTIN ANTIBODY; UNCLASSIFIED DRUG;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOCHEMICAL COMPOSITION; BIOSYNTHESIS; BONE DENSITY; BONE FRAGILITY; BONE MASS; BONE METABOLISM; BONE STRENGTH; CONTROLLED STUDY; FEMALE; GENE INACTIVATION; GENETIC DISORDER; MALE; MOUSE; NONHUMAN; OSSIFICATION; OSTEOPOROSIS PSEUDOGLIOMA SYNDROME; OSTEOSCLEROSIS; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN DETERMINATION; RARE DISEASE; SYNDROME;

ANIMALS; BONE AND BONES; BONE DEVELOPMENT; DISEASE MODELS, ANIMAL; GLYCOPROTEINS; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5; MICE; MICE, KNOCKOUT; ORGAN SIZE; OSTEOGENESIS IMPERFECTA;

EID: 84890094009     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3006627     Document Type: Article

References (52)

1. D. J. Becker, M. L. Kilgore, M. A. Morrisey, The societal burden of osteoporosis. Curr. Rheumatol. Rep. 12, 186-191 (2010).
2. R. Burge, B. Dawson-Hughes, D. H. Solomon, J. B. Wong, A. King, A. Tosteson, Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J. Bone Miner. Res. 22, 465-475 (2007).
3. J. Robbins, A. K. Aragaki, C. Kooperberg, N. Watts, J. Wactawski-Wende, R. D. Jackson, M. S. LeBoff, C. E. Lewis, Z. Chen, M. L. Stefanick, J. Cauley, Factors associated with 5-year risk of hip fracture in postmenopausal women. JAMA 298, 2389-2398 (2007).
4. Y. Gong, R. B. Slee, N. Fukai, G. Rawadi, S. Roman-Roman, A. M. Reginato, H. Wang, T. Cundy, F. H. Glorieux, D. Lev, M. Zacharin, K. Oexle, J. Marcelino, W. Suwairi, S. Heeger, G. Sabatakos, S. Apte, W. N. Adkins, J. Allgrove, M. Arslan-Kirchner, J. A. Batch, P. Beighton, G. C. Black, R. G. Boles, L. M. Boon, C. Borrone, H. G. Brunner, G. F. Carle, B. Dallapiccola, A. De Paepe, B. Floege, M. L. Halfhide, B. Hall, R. C. Hennekam, T. Hirose, A. Jans, H. Jüppner, C. A. Kim, K. Keppler-Noreuil, A. Kohlschuetter, D. LaCombe, M. Lambert, E. Lemyre, T. Letteboer, L. Peltonen, R. S. Ramesar, M. Romanengo, H. Somer, E. Steichen-Gersdorf, B. Steinmann, B. Sullivan, A. Superti-Furga, W. Swoboda, M. J. van den Boogaard, W. Van Hul, M. Vikkula, M. Votruba, B. Zabel, T. Garcia, R. Baron, B. R. Olsen, M. L. Warman; Osteoporosis-Pseudoglioma Syndrome Collaborative Group, LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513-523 (2001).
5. A. Saarinen, T. Saukkonen, T. Kivelä, U. Lahtinen, C. Laine, M. Somer, S. Toiviainen-Salo, W. G. Cole, A. E. Lehesjoki, O. Mäkitie, Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin. Endocrinol. 72, 481-488 (2010).
6. H. P. Arantes, E. R. Barros, I. Kunii, J. P. Bilezikian, M. Lazaretti-Castro, Teriparatide increases bone mineral density in a man with osteoporosis pseudoglioma. J. Bone Miner. Res. 26, 2823-2826 (2011).
7. E. A. Streeten, D. McBride, E. Puffenberger, M. E. Hoffman, T. I. Pollin, P. Donnelly, P. Sack, H. Morton, Osteoporosis-pseudoglioma syndrome: Description of 9 new cases and beneficial response to bisphosphonates. Bone 43, 584-590 (2008).
8. M. Kato, M. S. Patel, R. Levasseur, I. Lobov, B. H. Chang, D. A. Glass II, C. Hartmann, L. Li, T. H. Hwang, C. F. Brayton, R. A. Lang, G. Karsenty, L. Chan, 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 (2002).
9. K. Sawakami, A. G. Robling, M. Ai, N. D. Pitner, D. Liu, S. J. Warden, J. Li, P. Maye, D. W. Rowe, R. L. Duncan, M. L. Warman, C. H. Turner, 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 (2006).
10. S. L. Holmen, T. A. Giambernardi, C. R. Zylstra, B. D. Buckner-Berghuis, J. H. Resau, J. F. Hess, V. Glatt, M. L. Bouxsein, M. Ai, M. L. Warman, B. O. Williams, Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J. Bone Miner. Res. 19, 2033-2040 (2004).
11. X. Li, K. S. Warmington, Q. T. Niu, F. J. Asuncion, D. Dwyer, M. Grisanti, C.-Y. Han, P. J. Kostenuik, M. Stolina, M. S. Ominsky, H. Z. Ke, Increased bone mass and bone strength by sclerostin antibody is maintained by a RANKL inhibitor in ovariectomized rats with established osteopenia. J. Bone Miner. Res. 27 (Suppl. 1) (2012).
12. A. H. van Lierop, N. A. Hamdy, M. E. van Egmond, E. Bakker, F. G. Dikkers, S. E. Papapoulos, Van Buchem disease: Clinical, biochemical, and densitometric features of patients and disease carriers. J. Bone Miner. Res. 28, 848-854 (2012).
13. E. Bourhis, W. Wang, C. Tam, J. Hwang, Y. Zhang, D. Spittler, O. W. Huang, Y. Gong, A. Estevez, I. Zilberleyb, L. Rouge, C. Chiu, Y. Wu, M. Costa, R. N. Hannoush, Y. Franke, A. G. Cochran, Wnt antagonists bind through a short peptide to the first b-propeller domain of LRP5/6. Structure 19, 1433-1442 (2011).
14. X. Li, Y. Zhang, H. Kang, W. Liu, P. Liu, J. Zhang, S. E. Harris, D. Wu, Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883-19887 (2005).
15. W. Balemans, E. Piters, E. Cleiren, M. Ai, L. Van Wesenbeeck, M. L. Warman, W. Van Hul, The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif. Tissue Int. 82, 445-453 (2008).
16. M. V. Semenov, X. He, LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276-38284 (2006).
17. M. Semënov, K. Tamai, X. He, SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280, 26770-26775 (2005).
18. D. L. Ellies, B. Viviano, J. McCarthy, J. P. Rey, N. Itasaki, S. Saunders, R. Krumlauf, Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738-1749 (2006).
19. K. S. Joeng, C. A. Schumacher, C. R. Zylstra-Diegel, F. Long, B. O. Williams, Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev. Biol. 359, 222-229 (2011).
20. B. T. MacDonald, M. V. Semenov, H. Huang, X. He, Dissecting molecular differences between Wnt coreceptors LRP5 and LRP6. PLoS One 6, e23537 (2011).
21. M. S. Ominsky, C. Li, X. Li, H. L. Tan, E. Lee, M. Barrero, F. J. Asuncion, D. Dwyer, C. Y. Han, F. Vlasseros, R. Samadfam, J. Jolette, S. Y. Smith, M. Stolina, D. L. Lacey, W. S. Simonet, C. Paszty, G. Li, H. Z. Ke, Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J. Bone Miner. Res. 26, 1012-1021 (2011).
22. X. Tian, W. S. Jee, X. Li, C. Paszty, H. Z. Ke, Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone 48, 197-201 (2011).
23. X. Tian, R. B. Setterberg, X. Li, C. Paszty, H. Z. Ke, W. S. Jee, Treatment with a sclerostin antibody increases cancellous bone formation and bone mass regardless of marrow composition in adult female rats. Bone 47, 529-533 (2010).
24. U. M. Ayturk, C. M. Jacobsen, D. C. Christodoulou, J. Gorham, J. G. Seidman, C. E. Seidman, A. G. Robling, M. L. Warman, An RNA-seq protocol to identify mRNA expression changes in mouse diaphyseal bone: Applications in mice with bone property altering Lrp5 mutations. J. Bone Miner. Res. 28, 2081-2093 (2013).
25. D. Lev, I. Binson, A. J. Foldes, N. Watemberg, T. Lerman-Sagie, Decreased bone density in carriers and patients of an Israeli family with the osteoporosis-pseudoglioma syndrome. Isr. Med. Assoc. J. 5, 419-421 (2003).
26. M. Shahnazari, T. Wronski, V. Chu, A. Williams, A. Leeper, M. Stolina, H. Z. Ke, B. Halloran, Early response of bone marrow osteoprogenitors to skeletal unloading and sclerostin antibody. Calcif. Tissue Int. 91, 50-58 (2012).
27. J. M. Spatz, R. Ellman, A. M. Cloutier, L. Louis, M. van Vliet, L. J. Suva, D. Dwyer, M. Stolina, H. Z. Ke, M. L. Bouxsein, Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J. Bone Miner. Res. 28, 865-874 (2013).
28. D. G. Winkler, M. K. Sutherland, J. C. Geoghegan, C. Yu, T. Hayes, J. E. Skonier, D. Shpektor, M. Jonas, B. R. Kovacevich, K. Staehling-Hampton, M. Appleby, M. E. Brunkow, J. A. Latham, Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 22, 6267-6276 (2003).
29. D. G. Winkler, M. S. Sutherland, E. Ojala, E. Turcott, J. C. Geoghegan, D. Shpektor, J. E. Skonier, C. Yu, J. A. Latham, Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins. J. Biol. Chem. 280, 2498-2502 (2005).
30. P. Babij, W. Zhao, C. Small, Y. Kharode, P. J. Yaworsky, M. L. Bouxsein, P. S. Reddy, P. V. Bodine, J. A. Robinson, B. Bhat, J. Marzolf, R. A. Moran, F. Bex, High bone mass in mice expressing a mutant LRP5 gene. J. Bone Miner. Res. 18, 960-974 (2003).
31. Y. Cui, P. J. Niziolek, B. T. MacDonald, C. R. Zylstra, N. Alenina, D. R. Robinson, Z. Zhong, S. Matthes, C. M. Jacobsen, R. A. Conlon, R. Brommage, Q. Liu, F. Mseeh, D. R. Powell, Q. M. Yang, B. Zambrowicz, H. Gerrits, J. A. Gossen, X. He, M. Bader, B. O. Williams, M. L. Warman, A. G. Robling, Lrp5 functions in bone to regulate bone mass. Nat. Med. 17, 684-691 (2011).
32. C. M. Laine, B. D. Chung, M. Susic, T. Prescott, O. Semler, T. Fiskerstrand, P. D'Eufemia, M. Castori, M. Pekkinen, E. Sochett, W. G. Cole, C. Netzer, O. Mäkitie, Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG). Eur. J. Hum. Genet. 19, 875-881 (2011).
33. F. Bayram, F. Tanriverdi, S. Kurtoǧlu, M. E. Atabek, M. Kula, L. Kaynar, F. Keleştimur, Effects of 3 years of intravenous pamidronate treatment on bone markers and bone mineral density in a patient with osteoporosis-pseudoglioma syndrome (OPPG). J. Pediatr. Endocrinol. Metab. 19, 275-279 (2006).
34. B. Tüysüz, A. Bursali, Z. Alp, N. Suyugül, C. M. Laine, O. Mäkitie, Osteoporosis-pseudoglioma syndrome: Three novel mutations in the LRP5 gene and response to bisphosphonate treatment. Horm. Res. Paediatr. 77, 115-120 (2012).
35. G. Holdsworth, P. Slocombe, C. Doyle, B. Sweeney, V. Veverka, K. Le Riche, R. J. Franklin, J. Compson, D. Brookings, J. Turner, J. Kennedy, R. Garlish, J. Shi, L. Newnham, D. McMillan, M. Muzylak, M. D. Carr, A. J. Henry, T. Ceska, M. K. Robinson, Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors. J. Biol. Chem. 287, 26464-26477 (2012).
36. T. Kubota, T. Michigami, N. Sakaguchi, C. Kokubu, A. Suzuki, N. Namba, N. Sakai, S. Nakajima, K. Imai, K. Ozono, Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J. Bone Miner. Res. 23, 1661-1671 (2008).
37. X. Li, M. S. Ominsky, K. S. Warmington, S. Morony, J. Gong, J. Cao, Y. Gao, V. Shalhoub, B. Tipton, R. Haldankar, Q. Chen, A. Winters, T. Boone, Z. Geng, Q. T. Niu, H. Z. Ke, P. J. Kostenuik, W. S. Simonet, D. L. Lacey, C. Paszty, Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578-588 (2009).
38. M. R. McClung, A. Grauer, S. Boonen, J. P. Brown, A. Diez-Perez, B. Langdahl, J.-Y. Reginster, J. R. Zanchetta, L. Katz, J. Maddox, Y.-C. Yang, C. Libanati, H. G. Bone, Inhibition of sclerostin with AMG 785 in postmenopausal women with low bone mineral density: Phase 2 trial results. J. Bone Miner. Res. 27 (Suppl. 1) (2012).
39. D. Padhi, G. Jang, B. Stouch, L. Fang, E. Posvar, Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26, 19-26 (2011).
40. M. K. Chang, I. Kramer, H. Keller, J. H. Gooi, C. Collett, D. Jenkins, S. A. Ettenberg, F. Cong, C. Halleux, M. Kneissel, Reversing LRP5-dependent osteoporosis and SOST-deficiency induced sclerosing bone disorders by altering WNT signaling activity. J. Bone Miner. Res. 10.1002/jbmr.2059 (2013).
41. H. Y. Choi, M. Dieckmann, J. Herz, A. Niemeier, 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 (2009).
42. T. A. Craig, R. Bhattacharya, D. Mukhopadhyay, R. Kumar, Sclerostin binds and regulates the activity of cysteine-rich protein 61. Biochem. Biophys. Res. Commun. 392, 36-40 (2010).
43. T. A. Craig, R. Kumar, Sclerostin-erbB-3 interactions: Modulation of erbB-3 activity by sclerostin. Biochem. Biophys. Res. Commun. 402, 421-424 (2010).
44. H. Devarajan-Ketha, T. A. Craig, B. J. Madden, H. Robert Bergen III, R. Kumar, The sclerostinbone protein interactome. Biochem. Biophys. Res. Commun. 417, 830-835 (2012).
45. D. G. Winkler, C. Yu, J. C. Geoghegan, E. W. Ojala, J. E. Skonier, D. Shpektor, M. K. Sutherland, J. A. Latham, Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J. Biol. Chem. 279, 36293-36298 (2004).
46. O. Leupin, E. Piters, C. Halleux, S. Hu, I. Kramer, F. Morvan, T. Bouwmeester, M. Schirle, M. Bueno-Lozano, F. J. Fuentes, P. H. Itin, E. Boudin, F. de Freitas, K. Jennes, B. Brannetti, N. Charara, H. Ebersbach, S. Geisse, C. X. Lu, A. Bauer, W. Van Hul, M. Kneissel, Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J. Biol. Chem. 286, 19489-19500 (2011).
47. U. T. Iwaniec, T. J. Wronski, J. Liu, M. F. Rivera, R. R. Arzaga, G. Hansen, R. Brommage, PTH stimulates bone formation in mice deficient in Lrp5. J. Bone Miner. Res. 22, 394-402 (2007).
48. A. G. Robling, R. Kedlaya, S. N. Ellis, P. J. Childress, J. P. Bidwell, T. Bellido, C. H. Turner, Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 152, 2963-2975 (2011).
49. X. Li, M. S. Ominsky, Q. T. Niu, N. Sun, B. Daugherty, D. D'Agostin, C. Kurahara, Y. Gao, J. Cao, J. Gong, F. Asuncion, M. Barrero, K. Warmington, D. Dwyer, M. Stolina, S. Morony, I. Sarosi, P. J. Kostenuik, D. L. Lacey, W. S. Simonet, H. Z. Ke, C. Paszty, Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J. Bone Miner. Res. 23, 860-869 (2008).
50. A. M. Parfitt, M. K. Drezner, F. H. Glorieux, J. A. Kanis, H. Malluche, P. J. Meunier, S. M. Ott, R. R. Recker, Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 2, 595-610 (1987).
51. P. J. Niziolek, T. L. Farmer, Y. Cui, C. H. Turner, M. L. Warman, A. G. Robling, High-bone-massproducing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. Bone 49, 1010-1019 (2011).
52. C. H. Turner, D. B. Burr, Basic biomechanical measurements of bone: A tutorial. Bone 14, 595-608 (1993).