Stewart T L, Roschger P, Misof B M, Mann V, Fratzl P, Klaushofer K, Aspden R, Ralston S H
Department of Medicine and Therapeutics, University of Aberdeen Medical School, Aberdeen, AB25 2ZD, UK.
Calcif Tissue Int. 2005 Aug;77(2):113-8. doi: 10.1007/s00223-004-0188-8. Epub 2005 May 19.
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.
先前的研究发现，COLIA1基因调控区域存在一个影响Sp1结合位点的G/T多态性，该多态性通过部分独立于骨矿物质密度（BMD）差异的机制影响骨强度，从而导致骨质疏松性骨折。为了阐明COLIA1 Sp1等位基因影响骨强度的机制，我们使用定量背散射电子成像（qBEI）来表征不同COLIA1基因型受试者活检样本中的骨矿化情况，并研究了不同基因型受试者培养的成骨样细胞形成矿化骨结节的能力。qBEI分析显示，与G/G纯合子（n = 7）相比，G/T杂合子（n = 6）的骨活检样本矿化显著减少（P = 0.014），矿化异质性显著增加（P = 0.017）。体外研究表明，在所有检测的时间点，来自G/T杂合子（n = 5）的成骨细胞形成矿化骨结节的能力均显著低于G/G纯合子（n = 10）（P < 0.0001）。我们得出结论，COLIA1 Sp1“T”等位基因的携带与成骨样细胞在体外形成矿化骨结节的能力受损以及体内骨矿化异常有关。这表明COLIA1 Sp1等位基因携带者骨脆性增加可能部分源于骨矿化缺陷。
