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Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women

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Abstract

HTRA1 (high-temperature requirement A1) has been implicated in the modulation of various disease pathologies. HTRA1 expression is upregulated in osteoarthritic joints, suggesting that it may contribute to the development of this debilitating disease. Moreover, recent reports have shown that the rs11200638, a single nucleotide polymorphism (SNP) in the promoter region of the HTRA1 gene, is strongly associated with an increased prevalence of age-related macular degeneration (AMD). In the present study, we examined the expression of the HTRA1 in human primary chondrocytes and an association between the rs11200638 SNP and radiographic features of spinal disc degeneration in 513 postmenopausal Japanese women. HTRA1 mRNA was detected and increased by TGF-β treatment in human primary chondrocytes. As an association study of rs11200638 SNP in the HTRA1 gene, the subjects without the G allele (AA; n = 89) had a significantly higher spinal disc space narrowing score than the subjects bearing at least one G allele (GG + GA; n = 424) (P = 0.0292). We found that subjects without the G allele (AA) were significantly overrepresented in the subjects having a higher (≥4) disc space narrowing score (P = 0.013; odds ratio 1.97; 95% confidence interval 1.15–3.37 by logistic regression analysis). A genetic variation at the HTRA1 gene promoter locus is associated with spinal disc degeneration, suggesting an involvement of the HTRA1 gene in osteoarthritis.

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References

  1. Creamer P, Hochberg MC (1997) Osteoarthritis. Lancet 350:503–508

    Article  CAS  PubMed  Google Scholar 

  2. Lane NE, Nevitt MC, Genant HK, Hochberg MC (1993) Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration. J Rheumatol 20:1911–1918

    CAS  PubMed  Google Scholar 

  3. O’Neill TW, McCloskey EV, Kanis JA, Bhalla AK, Reeve J, Reid DM, Todd C, Woolf AD, Silman AJ (1999) The distribution, determinants, and clinical correlates of vertebral osteophytosis: a population based survey. J Rheumatol 26:842–848

    PubMed  Google Scholar 

  4. Spector TD, MacGregor AJ (2004) Risk factors for osteoarthritis: genetics. Osteoarthr Cartil 12:S39–S44

    Article  PubMed  Google Scholar 

  5. Loughlin J (2003) Genetics of osteoarthritis and potential for drug development. Curr Opin Pharmacol 3:295–299

    Article  CAS  PubMed  Google Scholar 

  6. Videman T, Leppävuori J, Kaprio J, Battié MC, Gibbons LE, Peltonen L, Koskenvuo M (1998) Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine 23:2477–2485

    Article  CAS  PubMed  Google Scholar 

  7. Jones G, White C, Sambrook P, Eisman J (1998) Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease. Ann Rheum Dis 57:94–99

    Article  CAS  PubMed  Google Scholar 

  8. Videman T, Gibbons LE, Battié MC, Maravilla K, Vanninen E, Leppävuori J, Kaprio J, Peltonen L (2001) The relative roles of intragenic polymorphisms of the vitamin d receptor gene in lumbar spine degeneration and bone density. Spine 26:E7–E12

    Article  CAS  PubMed  Google Scholar 

  9. Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T (2002) The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Jt Surg Am 84:2022–2028

    Google Scholar 

  10. Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ (2006) Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine 31:1143–1148

    Article  PubMed  Google Scholar 

  11. Clausen T, Southan C, Ehrmann M (2002) The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell 10:443–455

    Article  CAS  PubMed  Google Scholar 

  12. Spiess C, Beil A, Ehrmann M (1999) A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97:339–347

    Article  CAS  PubMed  Google Scholar 

  13. Canfield AE, Hadfield KD, Rock CF, Wylie EC, Wilkinson FL (2007) HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans 35:669–671

    Article  CAS  PubMed  Google Scholar 

  14. Baldi A, De Luca A, Morini M, Battista T, Felsani A, Baldi F, Catricalà C, Amantea A, Noonan DM, Albini A, Natali PG, Lombardi D, Paggi MG (2002) The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21:6684–6688

    Article  CAS  PubMed  Google Scholar 

  15. Chien J, Staub J, Hu SI, Erickson-Johnson MR, Couch FJ, Smith DI, Crowl RM, Kaufmann SH, Shridhar V (2004) A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 23:1636–1644

    Article  CAS  PubMed  Google Scholar 

  16. Chien J, Aletti G, Baldi A, Catalano V, Muretto P, Keeney GL, Kalli KR, Staub J, Ehrmann M, Cliby WA, Lee YK, Bible KC, Hartmann LC, Kaufmann SH, Shridhar V (2006) Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. J Clin Invest 116:1994–2004

    Article  CAS  PubMed  Google Scholar 

  17. Bakay M, Zhao P, Chen J, Hoffman EP (2002) A web-accessible complete transcriptome of normal human and DMD muscle. Neuromusc Disord 12:S125–S141

    Article  PubMed  Google Scholar 

  18. Hu SI, Carozza M, Klein M, Nantermet P, Luk D, Crowl RM (1998) Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage. J Biol Chem 273:34406–34412

    Article  CAS  PubMed  Google Scholar 

  19. Grau S, Richards PJ, Kerr B, Hughes C, Caterson B, Williams AS, Junker U, Jones SA, Clausen T, Ehrmann M (2006) The role of human HtrA1 in arthritic disease. J Biol Chem 281:6124–6129

    Article  CAS  PubMed  Google Scholar 

  20. Wu J, Liu W, Bemis A, Wang E, Qiu Y, Morris EA, Flannery CR, Yang Z (2007) Comparative proteomic characterization of articular cartilage tissue from normal donors and patients with osteoarthritis. Arthritis Rheum 56:3675–3684

    Article  CAS  PubMed  Google Scholar 

  21. Tocharus J, Tsuchiya A, Kajikawa M, Ueta Y, Oka C, Kawaichi M (2004) Developmentally regulated expression of mouse HtrA3 and its role as an inhibitor of TGF-β signaling. Dev Growth Differ 46:257–274

    Article  CAS  PubMed  Google Scholar 

  22. Murwantoko YanoM, Ueta Y, Murasaki A, Kanda H, Oka C, Kawaichi M (2004) Binding of proteins to the PDZ domain regulates proteolytic activity of HtrA1 serine protease. Biochem J 381:895–904

    Article  CAS  PubMed  Google Scholar 

  23. Tsuchiya A, Yano M, Tocharus J, Kojima H, Fukumoto M, Kawaichi M, Oka C (2005) Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. Bone (NY) 37:323–336

    CAS  Google Scholar 

  24. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989–992

    Article  CAS  PubMed  Google Scholar 

  25. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314:992–993

    Article  CAS  PubMed  Google Scholar 

  26. Mori K, Horie-Inoue K, Kohda M, Kawasaki I, Gehlbach PL, Awata T, Yoneya S, Okazaki Y, Inoue S (2007) Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population. J Hum Genet 52:636–641

    Article  CAS  PubMed  Google Scholar 

  27. Lotery A, Trump D (2007) Progress in defining the molecular biology of age related macular degeneration. Hum Genet 122:219–236

    Article  PubMed  Google Scholar 

  28. Urano T, Shiraki M, Ouchi Y, Inoue S (2007) Association of a single nucleotide polymorphism in the steroid and xenobiotic receptor (SXR) gene (IVS1–579A/G) with bone mineral density. Geriatr Gerontol Int 7:104–109

    Article  Google Scholar 

  29. Usui T, Urano T, Shiraki M, Ouchi Y, Inoue S (2007) Association of a single nucleotide polymorphism in Wnt10b gene with bone mineral density. Geriatr Gerontol Int 7:48–53

    Article  Google Scholar 

  30. Yu W, Glüer CC, Fuerst T, Grampp S, Li J, Lu Y, Genant HK (1995) Influence of degenerative joint disease on spinal bone mineral measurements in postmenopausal women. Calcif Tissue Int 57:169–174

    Article  CAS  PubMed  Google Scholar 

  31. Urano T, Shiraki M, Narusawa K, Usui T, Sasaki N, Hosoi T, Ouchi Y, Nakamura T, Inoue S (2007) Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese women. Spine 32:25–29

    Article  PubMed  Google Scholar 

  32. Urano T, Narusawa K, Shiraki M, Usui T, Sasaki N, Hosoi T, Ouchi Y, Nakamura T, Inoue S (2007) Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women. J Bone Miner Metab 25:253–258

    Article  CAS  PubMed  Google Scholar 

  33. Urano T, Narusawa K, Shiraki M, Usui T, Sasaki N, Hosoi T, Ouchi Y, Nakamura T, Inoue S (2008) Association of a single nucleotide polymorphism in the insulin-like growth factor-1 receptor gene with spinal disc degeneration in postmenopausal Japanese women. Spine 33:1256–1261

    Article  PubMed  Google Scholar 

  34. Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi T, Orimo H, Ouchi Y, Inoue S (2004) Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density. Geriatr Gerontol Int 4:175–180

    Article  Google Scholar 

  35. Klein R, Peto T, Bird A, Vannewkirk MR (2004) The epidemiology of age-related macular degeneration. Am J Ophthalmol 137:486–495

    Article  PubMed  Google Scholar 

  36. Mullins RF (2007) Genetic insights into the pathobiology of age-related macular degeneration. Int Ophthalmol Clin 47:1–14

    Article  PubMed  Google Scholar 

  37. Ross RJ, Verma V, Rosenberg KI, Chan CC, Tuo J (2007) Genetic markers and biomarkers for age-related macular degeneration. Expert Rev Ophthalmol 2:443–457

    Article  CAS  PubMed  Google Scholar 

  38. Age-Related Eye Disease Study Research Group (2000) Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 107:2224–2232

    Article  Google Scholar 

  39. Zlateva GP, Javitt JC, Shah SN, Zhou Z, Murphy JG (2007) Comparison of comorbid conditions between neovascular age-related macular degeneration patients and a control cohort in the medicare population. Retina 27:1292–1299

    Article  PubMed  Google Scholar 

  40. Klein R, Knudtson MD, Klein BE, Wong TY, Cotch MF, Liu K, Cheng CY, Burke GL, Saad MF, Jacobs DR Jr, Sharrett AR (2008) Inflammation, complement factor H, and age-related macular degeneration: The Multi-Ethnic Study of Atherosclerosis. Ophthalmology 115:1742–1749

    Article  PubMed  Google Scholar 

  41. Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M (2004) HtrA1 serine protease inhibits signaling mediated by Tgfβ family proteins. Development 131:1041–1053

    Article  CAS  PubMed  Google Scholar 

  42. Seddon JM, Ajani UA, Mitchell BD (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 123:199–206

    CAS  PubMed  Google Scholar 

  43. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 104:16227–16232

    Article  CAS  PubMed  Google Scholar 

  44. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, Weber BH (2008) Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 40:892–896

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Ms. M. Iwashita for her expert technical assistance. This work was partly supported by a grant from the Japanese Osteoporosis Foundation. This work was partly supported by grants from the Japanese Ministry of Health, Labor, Welfare and Japan Society for the Promotion of Science and a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We appreciate all the volunteers and participating institutions for precious clinical data and samples.

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Authors and Affiliations

  1. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Tomohiko Urano, Satomi Kobayashi, Noriko Sasaki, Yasuyoshi Ouchi & Satoshi Inoue

  2. Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Tomohiko Urano, Satomi Kobayashi, Noriko Sasaki & Satoshi Inoue

  3. Research Center for Genomic Medicine, Saitama Medical School, 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

    Tomohiko Urano, Kuniko Horie-Inoue & Satoshi Inoue

  4. Department of Orthopedic Surgery, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

    Ken’ichiro Narusawa & Toshitaka Nakamura

  5. Research Institute and Practice for Involutional Diseases, 1609 Meisei, Misato-mura, Minami-Azumi-gun, Nagano, 399-8101, Japan

    Masataka Shiraki

  6. Department of Advanced Medicine, National Center for Geriatrics and Gerontology, Aichi, Japan

    Takayuki Hosoi

Authors
  1. Tomohiko Urano
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  2. Ken’ichiro Narusawa
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  3. Satomi Kobayashi
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  4. Masataka Shiraki
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  5. Kuniko Horie-Inoue
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  7. Takayuki Hosoi
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  8. Yasuyoshi Ouchi
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  9. Toshitaka Nakamura
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  10. Satoshi Inoue
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Correspondence to Satoshi Inoue.

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Urano, T., Narusawa, K., Kobayashi, S. et al. Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women. J Bone Miner Metab 28, 220–226 (2010). https://doi.org/10.1007/s00774-009-0124-0

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  • DOI: https://doi.org/10.1007/s00774-009-0124-0

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