Kandidatengene und neue therapeutische Möglichkeiten für Osteoporose

B. Obermayer-Pietsch

doi:10.1055/s-0037-1619998

Osteologie, Table of Contents

Osteologie 2011; 20(03): 227-232
DOI: 10.1055/s-0037-1619998

Knochenzellbiologie und Osteoporosetherapie

Schattauer GmbH

Kandidatengene und neue therapeutische Möglichkeiten für Osteoporose

Candidate genes and new therapeutic options for osteoporosis

Authors

B. Obermayer-Pietsch

¹Klinische Abteilung und Labor für Endokrinologie und Stoffwechsel, §68-Einrichtung für Genanalysen, Universitäts- klinik für Innere Medizin, Medizinische Universität Graz, Österreich

Abstract

Zusammenfassung

Die genetischen Grundlagen der Osteoporose werden seit Langem intensiv beforscht. Bisher wurden bereits zahlreiche wichtige Kandidatengene für Knochendichte identifiziert – genetische Varianten in diesen Genen sind für einen Teil der individuellen Knochenmasse verantwortlich. Relevante Stoffwechselwege werden bereits für therapeutische Anwendungen genutzt. Aufgrund von neuen großangelegten genomweiten Assoziationsanalysen sind nun teils völlig neue Kandidatengene vorgestellt worden, die in Zukunft nicht nur Licht auf die komplexen pathophysiologischen Grundlagen der Osteoporose werfen werden, sondern auch für die Entwicklung neuer Therapeutika wichtig sein könnten.

Summary

The genetic background of osteoporosis has long been investigated. Several genetic loci have been identified, which have already been shown to be associated with an increased risk for low bone mineral density. Critical bone pathways out of these genes have been used to develop therapeutic applications. Based on huge genome-wide association studies, new candidate genes for bone mineral density and osteoporotic fractures have now been reported. They will not only shed light on the complex pathophysiological pathways of osteoporosis, but might also be the basis for the development of new therapeutic drugs for osteoporosis.

Schlüsselwörter

Kandidatengene - Polymorphismen - Osteoporose - GWAS

Keywords

Candidate gene - polymorphism - osteoporosis - GWAS

Full Text

References

Literatur
1 Peacock M, Turner CH, Econs MJ, Foroud T. Genetics of osteoporosis. Endocr Rev 2002; 23: 303-326.
2 Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev 2010; 31: 629-662.
3 Ioannidis JP. et al. Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 2007; 22: 173-183.
4 Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med 2009; 360: 1759-1768.
5 Rivadeneira F, Styrkársdottir U, Estrada K. et al.; Genetic Factors for Osteoporosis (GEFOS) Consortium. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 2009; 41 (11) 1199-1206.
6 Estrada C and the GEFOS and GENOMOS consortia. Association analyses of 47,500 individuals identifies six fracture loci and 82 BMD loci clustering in biological pathways that regulate osteoblast and osteoclast activity. Meeting of the Calcified Tissue Society. 2011
7 Klein RJ, Zeiss C, Chew EY. et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308 (5720): 385-389.
8 Sladek R, Rocheleau G, Rung J. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445 (7130): 881-885.
9 Johnson A, O’Donnell C. An open access database of genome-wide association results. BMC medical genetics 2009; 10: 6.
10 Ioannidis JP, Ralston SH, Bennett ST. et al.; GENOMOS Study. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 2004; 292 (17) 2105-2114.
11 Ralston SH, Uitterlinden AG, Brandi ML. et al. for the GENOMOS Study. Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS Study. PLoS Med 2006; 03: e90.
12 Uitterlinden AG, Ralston SH, Brandi ML. et al. Large-scale analysis of association between common vitamin D receptor gene variations and osteoporosis: The GENOMOS Study. Ann Intern Med 2006; 145 (04) 255-264.
13 van Meurs JB, Trikalinos TA, Ralston SH. et al.; GENOMOS Study. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. Jama 2008; 299: 1277-1290.
14 Matsuda A, Suzuki Y, Honda G. et al. Large-scale identification and characterization of human genes that activate NfkappaB and MAPK signalling pathways. Oncogene 2003; 22: 3307-3318.
15 Glass 2^nd DA, Bialek P, Ahn JD. et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005; 08: 751-764.
16 Potthoff MJ, Wu H, Arnold MA. et al. Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J Clin Invest 2007; 117: 2459-2467.
17 Cho YS, Go MJ, Kim YJ. et al. A large-scale genomewide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 2009; 41: 527-534.
18 Tang Y, Katuri V, Dillner A. et al. Disruption of transforming growth factor-beta signaling in ELF betaspectrin-deficient mice. Science 2003; 299: 574-577.
19 Smits P, Li P, Mandel J. et al. The Transcription Factors L-Sox5 and Sox6 Are Essential for Cartilage Formation. Dev Cell 2001; 01: 277-290.
20 Zhou G, Zheng Q, Engin F. et al. Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc Natl Acad Sci U S A 2006; 103: 19004-19009.
21 Reiner O, Coquelle FM, Peter B. et al. The evolving doublecortin (DCX) superfamily. BMC Genomics 2006; 07: 188.
22 Stankiewicz P, Sen P, Bhatt SS. et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 2009; 84: 780-791.
23 Winnier GE, Hargett L, Hogan BL. The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo. Genes Dev 1997; 11: 926-940.
24 Styrkarsdottir U, Halldorsson BV, Gretarsdottir S. et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med 2008; 358: 2355-2365.
25 Malaval L, Wade-Guéye NM, Boudiffa M. et al. Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med 2008; 205: 1145-1153.
26 Wang L, Yang L, Debidda M. et al. Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proc Natl Acad Sci U S A 2007; 104: 1248-1253.
27 Schroeder TM, Westendorf JJ. Histone deacetylase inhibitors promote osteoblast maturation. J Bone Miner Res 2005; 20: 2254-2263.
28 Obermayer-Pietsch BM, Bonelli CM, Walter DE. et al. Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res 2004; 19 (01) 42-47.
29 Högenauer C, Hammer HF, Mellitzer K. et al. Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur J Gastroenterol Hepatol 2005; 17 (03) 371-376.
30 Diarra D, Stolina M, Polzer K. et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007; 13: 156-163.
31 Heath DJ, Chantry AD, Buckle CH. et al. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 2009; 24: 425-436.
32 Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011; 377 (9773): 1276-1287.
33 Padhi D, Stouch B, Jang G. et al. Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women. J Bone Miner Res 2007; 22 (Suppl. 01) S37.
34 Hannon RA, Clack G, Rimmer M. et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J Bone Miner Res 2010; 25: 463-471.
35 Bone HG, McClung MR, Roux C. et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 2010; 25: 937-947.
36 Schaller S, Henriksen K, Sveigaard C. et al. The chloride channel inhibitor NS3736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 2004; 19: 1144-1153.