Skip to main content

Advertisement

SpringerLink
Log in

Relationship of COL9A1 and SOX9 Genes with Genetic Susceptibility of Postmenopausal Osteoporosis

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

As one of the most common types of osteoporosis, postmenopausal osteoporosis (PMOP) is caused by both genetic and environmental factors. Previous studies have indicated that SOX9 activity is tightly regulated to ensure normal bone mineral density (BMD) in the adult skeleton, and the COL9A1 promoter region can be transactivated by SOX9. In this study, we aimed to investigate the potential association between PMOP and the COL9A1 and SOX9 genes. A total of 10,443 postmenopausal women, including 2288 patients and 3557 controls in the discovery stage and 1566 patients and 3032 controls in the validation stage, were recruited. Forty-three tag SNPs (36 in COL9A1 and 7 in SOX9) were selected for genotyping to evaluate the association of the SOX9 gene with PMOP and BMD. Association and bioinformatics analyses were performed for PMOP. BMD and serum level of SOX9 were also utilized as quantitative phenotypes in further analyses. SNP rs73354570 of SOX9 was significantly associated with PMOP in both discovery stages (OR 1.24 [1.10–1.39], P = 3.56 × 10−4, χ2 = 12.75) and combined samples (OR 1.25 [1.15–1.37], P = 5.25 × 10−7, χ2 = 25.17). Further analyses showed that the SNP was also significantly associated with BMD and serum levels of the SOX9 protein. Our results provide further supportive evidence for the association of the SOX9 gene with PMOP and of the SOX9 gene with the variation of BMD in postmenopausal Han Chinese women. This study supports a role for SOX9 in the etiology of PMOP, adding to the current understanding of the susceptibility of osteoporosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Parfitt AM (1982) The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res 4:1–6

    CAS  PubMed  Google Scholar 

  2. Appelman-Dijkstra NM, Papapoulos SE (2015) Modulating bone resorption and bone formation in opposite directions in the treatment of postmenopausal osteoporosis. Drugs 75:1049–1058

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Soen S, Fukunaga M, Sugimoto T et al (2013) Diagnostic criteria for primary osteoporosis: year 2012 revision. J Bone Miner Metab 31:247–257

    PubMed  Google Scholar 

  4. Willson T, Nelson SD, Newbold J, Nelson RE, LaFleur J (2015) The clinical epidemiology of male osteoporosis: a review of the recent literature. Clin Epidemiol 7:65–76

    PubMed  PubMed Central  Google Scholar 

  5. Slemenda CW, Christian JC, Williams CJ et al (1991) Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates. J Bone Miner Res 6(6):561–567

    CAS  PubMed  Google Scholar 

  6. Flicker L, Hopper JL, Rodgers L et al (1995) Bone density determinants in elderly women: a twin study. J Bone Miner Res 10(11):1607–1613

    CAS  PubMed  Google Scholar 

  7. Hernandez-de Sosa N, Athanasiadis G, Malouf J et al (2014) Heritability of bone mineral density in a multivariate family-based study. Calcif Tissue Int 94(6):590–596

    CAS  PubMed  Google Scholar 

  8. Shang M, Lin L, Cui H (2013) Association of genetic polymorphisms of RANK, RANKL and OPG with bone mineral density in Chinese peri-and postmenopausal women. Clin Biochem 46(15):1493–1501

    CAS  PubMed  Google Scholar 

  9. Bandres E, Pombo I, Gonzalez-Huarriz M et al (2005) Association between bone mineral density and polymorphisms of the VDR, ERα, COL1A1 and CTR genes in Spanish postmenopausal women. J Endocrinol Investig 28(6):312–321

    CAS  Google Scholar 

  10. Morris JA, Kemp JP, Youlten SE et al (2019) An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet 51(2):258

    CAS  PubMed  Google Scholar 

  11. Estrada K, Styrkarsdottir U, Evangelou E et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kemp JP, Morris JA, Medina-Gomez C et al (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 49:1468–1475

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mafi Golchin M, Heidari L, Ghaderian SM, Akhavan-Niaki H (2016) Osteoporosis: a silent disease with complex genetic contribution. J Genet Genomics 43:49–61

    PubMed  Google Scholar 

  14. Wang CJ, Iida K, Egusa H, Hokugo A, Jewett A, Nishimura I (2008) Trabecular bone deterioration in col9a1+/- mice associated with enlarged osteoclasts adhered to collagen IX-deficient bone. J Bone Miner Res 23:837–849

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Parsons P, Gilbert SJ, Vaughan-Thomas A, Sorrell DA, Notman R, Bishop M, Hayes AJ, Mason DJ, Duance VC (2011) Type IX collagen interacts with fibronectin providing an important molecular bridge in articular cartilage. J Biol Chem 286:34986–34997

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Brachvogel B, Zaucke F, Dave K, Norris EL, Stermann J, Dayakli M, Koch M, Gorman JJ, Bateman JF, Wilson R (2013) Comparative proteomic analysis of normal and collagen IX null mouse cartilage reveals altered extracellular matrix composition and novel components of the collagen IX interactome. J Biol Chem 288:13481–13492

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Posey KL, Hankenson K, Veerisetty AC, Bornstein P, Lawler J, Hecht JT (2008) Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen. Am J Pathol 172:1664–1674

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mustafa Z, Chapman K, Irven C et al (2000) Linkage analysis of candidate genes as susceptibility loci for osteoarthritis—suggestive linkage of COL9A1 to female hip osteoarthritis. Rheumatology 39(3):299–306

    CAS  PubMed  Google Scholar 

  19. Shi X, Zhang F, Lv A et al (2015) COL9A1 gene polymorphism is associated with Kashin-Beck disease in a northwest Chinese Han population. PLoS ONE 10(3):e0120365

    PubMed  PubMed Central  Google Scholar 

  20. Akiyama H (2008) Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol 18:213–219

    CAS  PubMed  Google Scholar 

  21. Takeda K, Kou I, Otomo N et al (2019) A multiethnic meta-analysis defined the association of rs12946942 with severe adolescent idiopathic scoliosis. J Hum Genet 64(5):493

    PubMed  Google Scholar 

  22. Miyake A, Kou I, Takahashi Y et al (2013) Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS ONE 8(9):e72802

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Roosenboom J, Lee MK, Hecht JT et al (2018) Mapping genetic variants for cranial vault shape in humans. PLoS ONE 13(4):e0196148

    PubMed  PubMed Central  Google Scholar 

  24. Baird DA, Evans DS, Kamanu FK et al (2019) Identification of Novel loci associated with hip shape: a meta-analysis of genomewide association studies. J Bone Miner Res 34(2):241–251

    CAS  PubMed  Google Scholar 

  25. Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (2001) Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA 98:6698–6703

    CAS  PubMed  Google Scholar 

  26. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16(21):2813–2828

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang Y, Zhang X, Niu X et al (2019) The genetic relationship of SOX9 polymorphisms with osteoarthritis risk in Chinese population: a case-control study. Medicine 98(8):e14096

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Song Y, Du Z, Ren M et al (2016) Significant associations of SOX9 gene polymorphism and gene expression with the risk of osteonecrosis of the femoral head in a Han population in Northern China. BioMed Res Int. https://doi.org/10.1155/2016/5695317

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liang B, Cotter MM, Chen D, Hernandez CJ, Zhou G (2012) Ectopic expression of SOX9 in osteoblasts alters bone mechanical properties. Calcif Tissue Int 90:76–89

    CAS  PubMed  Google Scholar 

  30. Zhang L, Choi HJ, Estrada K et al (2013) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet 23(7):1923–1933

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Qin L, Liu Y, Wang Y, Wu G, Chen J, Ye W, Yang J, Huang Q (2016) Computational characterization of osteoporosis associated SNPs and genes identified by genome-wide association studies. PLoS ONE 11:e0150070

    PubMed  PubMed Central  Google Scholar 

  32. Zhang P, Jimenez SA, Stokes DG (2003) Regulation of human COL9A1 gene expression. Activation of the proximal promoter region by SOX9. J Biol Chem 278:117–123

    CAS  PubMed  Google Scholar 

  33. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    CAS  Google Scholar 

  34. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4:7

    PubMed  PubMed Central  Google Scholar 

  35. Xie D, Boyle AP, Wu L, Zhai J, Kawli T, Snyder M (2013) Dynamic trans-acting factor colocalization in human cells. Cell 155:713–724

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Consortium GT (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45:580–585

    Google Scholar 

  37. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B (2006) Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc Natl Acad Sci USA 103:19004–19009

    CAS  PubMed  Google Scholar 

  38. Song Y, Du Z, Ren M, Yang Q, Sui Y, Wang Q, Wang A, Zhao H, Wang J, Zhang G (2016) Significant associations of SOX9 gene polymorphism and gene expression with the risk of osteonecrosis of the femoral head in a han population in Northern China. BioMed Res Int 2016:5695317

    PubMed  PubMed Central  Google Scholar 

  39. Hattori T, Muller C, Gebhard S et al (2010) SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development 137:901–911

    CAS  PubMed  Google Scholar 

  40. Jensen ED, Nair AK, Westendorf JJ (2007) Histone deacetylase co-repressor complex control of Runx2 and bone formation. Crit Rev Eukaryot Gene Expr 17:187–196

    CAS  PubMed  Google Scholar 

  41. Xiao Z, Awad HA, Liu S, Mahlios J, Zhang S, Guilak F, Mayo MS, Quarles LD (2005) Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice. Dev Biol 283:345–356

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Guan F, Zhang B, Yan T, Li L, Liu F, Li T, Feng Z, Zhang B, Liu X, Li S (2014) MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophr Res 152(1):97–104

    PubMed  Google Scholar 

  43. Jia X, Zhang T, Li L, Fu D, Lin H, Chen G, Liu X, Guan F (2016) Two-stage additional evidence support association of common variants in the HDAC3 with the increasing risk of schizophrenia susceptibility. Am J Med Genet B 171(8):1105–1111

    CAS  Google Scholar 

  44. Zhang T, Zhu L, Ni T, Liu D, Chen G, Yan Z, Lin H, Guan F, Rice JP (2018) Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population. J Psychiatr Res 106:99–105

    PubMed  Google Scholar 

  45. Han W, Zhang T, Ni T, Zhu L, Liu D, Chen G, Lin H, Chen T, Guan F (2019) Relationship of common variants in CHRNA5 with early-onset schizophrenia and executive function. Schizophr Res 206:407–412

    PubMed  Google Scholar 

  46. Liu X, Hou Y, Yan T, Guo Y, Han W, Guan F, Chen T, Li T (2014) Dopamine D3 receptor-regulated NR2B subunits of N-methyl-d-aspartate receptors in the nucleus accumbens involves in morphine-induced locomotor activity. CNS Neurosci Ther 20(9):823–829

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu L, Li J, Dong N, Guan F, Liu Y, Ma D, Goh EL, Chen T (2016) mRNA changes in nucleus accumbens related to methamphetamine addiction in mice. Sci Rep 6:36993

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Li J, Zhu L, Guan F, Yan Z, Liu D, Han W, Chen T (2018) Relationship between schizophrenia and changes in the expression of the long non-coding RNAs Meg3, Miat, Neat1 and Neat2. J Psychiatr Res 106:22–30

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopedic, The First Affiliated Hospital of Xi’an Jiaotong University, No.277, Yanta West Road, Xi’an, 710061, Shaanxi, China

    Hongliang Liu

  2. Department of Trauma Orthopedics, Honghui Hospital, Xi’an Jiaotong University Health Science Center, No.555, Youyi East Road, Xi’an, 710054, Shaanxi, China

    Hongliang Liu, Hua Lin, Zhong Li & Hanzhong Xue

  3. Department of Foot and Ankle Surgery, Honghui Hospital, Xi’an Jiaotong University Health Science Center, No.555, Youyi East Road, Xi’an, 710054, Shaanxi, China

    Hongmou Zhao

  4. Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, No.157, Xiwu Road, Xi’an, 710004, Shaanxi, China

    Yunzhi Zhang

  5. Department of Internal Medicine, Honghui Hospital, Xi’an Jiaotong University Health Science Center, No.555, Youyi East Road, Xi’an, 710054, Shaanxi, China

    Jun Lu

Authors
  1. Hongliang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongmou Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hua Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hanzhong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yunzhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments: Jun Lu and Hongliang Liu. Performed the experiments: Hongliang Liu and Hongmou Zhao. Analyzed the data: Hua Lin. Contributed reagents / materials / analysis tools: Zhong Li, Hanzhong Xue and Yunzhi Zhang. Wrote the paper: Hongliang Liu.

Corresponding author

Correspondence to Jun Lu.

Ethics declarations

Conflict of interest

Hongliang Liu, Hongmou Zhao, Hua Lin, Zhong Li, Hanzhong Xue, Yunzhi Zhang and Jun Lu declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This study was performed in accordance with the ethical guidelines of the Helsinki Declaration of 1975 (revised in 2008) and was approved by the Medical Ethics Committee of Honghui Hospital of Xi’an Jiaotong University. Informed consent was obtained from all subjects.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 575 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, H., Zhao, H., Lin, H. et al. Relationship of COL9A1 and SOX9 Genes with Genetic Susceptibility of Postmenopausal Osteoporosis. Calcif Tissue Int 106, 248–255 (2020). https://doi.org/10.1007/s00223-019-00629-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-019-00629-7

Keywords

Search

Navigation