Skip to main content
SpringerLink
Log in

Association of COLIA1 Sp1 Alleles with Defective Bone Nodule Formation In Vitro and Abnormal Bone Mineralization In Vivo

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Previous work identified a G/T polymorphism affecting a Sp1 binding site in a regulatory region of the COLIA1 gene that predisposes to osteoporotic fractures by affecting bone strength through mechanisms that are partly independent of differences in bone mineral density (BMD). To clarify the mechanisms by which COLIA1 Sp1 alleles influence bone strength we used quantitative backscattered electron imaging (qBEI) to characterize bone mineralization in biopsy samples from subjects of different COLIA1 genotype and studied the ability of osteoblast-like cells cultured from subjects of different genotypes to form mineralized bone nodules. The qBEI analysis showed a significant (P = 0.014) reduction in mineralization in bone biopsies from G/T heterozygotes (n = 6) compared with G/G homozygotes (n = 7) and a significant increase in heterogeneity of mineralization (P = 0.017). The in vitro studies showed that osteoblasts derived from G/T heterozygotes (n = 5) were significantly less able to produce mineralized bone nodules than G/G homozygotes (n = 10) at all time-points examined (P < 0.0001). We conclude that carriage of the COLIA1 Sp1 “T” allele is associated with an impaired ability of osteoblast-like cells to form mineralized bone nodules in vitro and with abnormalities of bone mineralization in vivo. This suggests that the increased bone fragility in carriers of the COLIA1 Sp1 allele may result in part from defects in bone mineralization.

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. JA Kanis LJ Melton SuffixIII C Christiansen CC Johnston N Khaltaev (1994) ArticleTitleThe diagnosis of osteoporosis J Bone Miner Res 9 1137–1141 Occurrence Handle7976495

    PubMed  Google Scholar 

  2. Z Efstathiadou A Tsatsoulis JP Ioannidis (2001) ArticleTitleAssociation of collagen I alpha 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis J Bone Miner Res 16 1586–1592 Occurrence Handle11547828

    PubMed  Google Scholar 

  3. V Mann SH Ralston (2003) ArticleTitleMeta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture Bone 32 711–717 Occurrence Handle10.1016/S8756-3282(03)00087-5 Occurrence Handle12810179

    Article  PubMed  Google Scholar 

  4. P Bornstein J McKay (1988) ArticleTitleThe first intron of the alpha 1(I) collagen gene contains several transcriptional regulatory elements J Biol Chem 263 1603–1606 Occurrence Handle2828347

    PubMed  Google Scholar 

  5. V Mann EE Hobson B Li TL Stewart SF Grant SP Robins RM Aspden SH Ralston (2001) ArticleTitleA COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality J.Clin Invest 107 899–907 Occurrence Handle11285309

    PubMed  Google Scholar 

  6. FE McGuigan DM Reid SH Ralston (2000) ArticleTitleSusceptibility to osteoporotic fracture is determined by allelic variation at the Sp1 site, rather than other polymorphic sites at the COL1A1 locus Osteoporos Int 11 338–343 Occurrence Handle10.1007/s001980070123 Occurrence Handle10928224

    Article  PubMed  Google Scholar 

  7. P Roschger P Fratzl J Eschberger K Klaushofer (1998) ArticleTitleValidation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies [see comments] Bone 23 319–326 Occurrence Handle10.1016/S8756-3282(98)00112-4 Occurrence Handle9763143

    Article  PubMed  Google Scholar 

  8. P Roschger H Plenk SuffixJr. K Klaushofer J Eschberger (1995) ArticleTitleA new scanning electron microscopy approach to the quantification of bone mineral distribution: backscattered electron image grey-levels correlated to calcium K alpha-line intensities Scanning Microsc 9 75–86 Occurrence Handle8553027

    PubMed  Google Scholar 

  9. P Roschger HS Gupta A Berzlanovich G Ittner DW Dempster P Fratzl F Cosman M Parisien R Lindsay JW Nieves K Klaushofer (2003) ArticleTitleConstant mineralization density distribution in cancellous human bone Bone 32 316–323 Occurrence Handle10.1016/S8756-3282(02)00973-0 Occurrence Handle12667560

    Article  PubMed  Google Scholar 

  10. JN Beresford JA Gallacher M Gowen MKB McGuire J Poser RGG Russell (1983) ArticleTitleHuman bone cells in culture. A novel system for the investigation of bone cell metabolism Clin Sci 64 38–39

    Google Scholar 

  11. K Johnson S Hashimoto M Lotz K Pritzker J Goding R Terkeltaub (2001) ArticleTitleUp-regulated expression of the phosphodiesterase nucleotide pyrophosphatase family member PC-1 is a marker and pathogenic factor for knee meniscal cartilage matrix calcification Arthritis Rheum 44 1071–1081 Occurrence Handle10.1002/1529-0131(200105)44:5<1071::AID-ANR187>3.0.CO;2-3 Occurrence Handle11352238

    Article  PubMed  Google Scholar 

  12. P Roschger S Rinnerthaler J Yates GA Rodan P Fratzl K Klaushofer (2001) ArticleTitleAlendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women Bone 29 185–191 Occurrence Handle10.1016/S8756-3282(01)00485-9 Occurrence Handle11502482

    Article  PubMed  Google Scholar 

  13. Garnero (2000) ArticleTitleMarkers of bone turnover for the prediction of fracture risk Osteoporos Int 11 Suppl 6 S55–S65 Occurrence Handle10.1007/s001980070006

    Article  Google Scholar 

  14. RW Keen KL Woodford-Richens SF Grant SH Ralston JS Lanchbury TD Spector (1999) ArticleTitleAssociation of polymorphism at the type I collagen (COL1A1) locus with reduced bone mineral density, increased fracture risk, and increased collagen turnover Arthritis Rheum 42 285–290 Occurrence Handle10.1002/1529-0131(199902)42:2<285::AID-ANR10>3.0.CO;2-3 Occurrence Handle10025922

    Article  PubMed  Google Scholar 

  15. BL Langdahl SH Ralston SFA Grant EF Eriksen (1998) ArticleTitleAn Sp1 binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in men and women J Bone Miner Res 13 1384–1389 Occurrence Handle9738510

    PubMed  Google Scholar 

  16. AM Qureshi RJ Herd GM Blake I Fogelman SH Ralston (2002) ArticleTitleCOLIA1 Sp1 polymorphism predicts response of femoral neck bone density to cyclical etidronate therapy Calcif Tissue Int 70 158–163 Occurrence Handle10.1007/s00223-001-1035-9 Occurrence Handle11907712

    Article  PubMed  Google Scholar 

  17. GY Boivin PM Chavassieux AC Santora J Yates PJ Meunier (2000) ArticleTitleAlendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women Bone 27 687–694 Occurrence Handle10.1016/S8756-3282(00)00376-8 Occurrence Handle11062357

    Article  PubMed  Google Scholar 

  18. H Follet G Boivin C Rumelhart PJ Meunier (2004) ArticleTitleThe degree of mineralization is a determinant of bone strength: a study on human calcanei Bone 34 783–789 Occurrence Handle10.1016/j.bone.2003.12.012 Occurrence Handle15121009

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Therapeutics, University of Aberdeen Medical School, Aberdeen, AB25 2ZD, UK

    T. L. Stewart & R. Aspden

  2. Ludwig Boltzmann Institute of Osteology, 4th Med. Dept., Hanusch Hospital & UKH Meidling, Vienna, Austria

    P. Roschger, B. M. Misof & K. Klaushofer

  3. Max-Planck-Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam, 14424, Germany

    P. Fratzl

  4. Rheumatic Diseases Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH42XU, UK

    V. Mann & S. H. Ralston

Authors
  1. T. L. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Roschger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. M. Misof
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Fratzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Klaushofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Aspden
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. H. Ralston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. H. Ralston.

Additional information

T.L.S. and P.R. contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, T.L., Roschger, P., Misof, B.M. et al. Association of COLIA1 Sp1 Alleles with Defective Bone Nodule Formation In Vitro and Abnormal Bone Mineralization In Vivo . Calcif Tissue Int 77, 113–118 (2005). https://doi.org/10.1007/s00223-004-0188-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-004-0188-8

Keywords

Search

Navigation