Bouxsein Mary L, Uchiyama Toru, Rosen Clifford J, Shultz Kathryn L, Donahue Leah R, Turner Charles H, Sen Saunak, Churchill Gary A, Müller Ralph, Beamer Wesley G
Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Bone Miner Res. 2004 Apr;19(4):587-99. doi: 10.1359/JBMR.0301255. Epub 2003 Dec 22.
BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome-wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton.
Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture.
To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High-resolution microCT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H-F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR-based markers discriminating B6 and C3H alleles on all 19 autosomes.
Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (-53%) and Tb.N (-40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome-wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22-33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebral trabecular bone volume fraction and microarchitecture using the F2 intercross of the C57BL/6J and C3H/HeJ inbred mouse strains and identified a number of QTLs, some of which are distinct from those that were previously identified for total femoral and vertebral BMD. Identification of genes that regulate trabecular bone traits may ultimately yield important information regarding the mechanisms that regulate the acquisition and maintenance of mechanical integrity of the skeleton.
骨密度(BMD)反映皮质骨和松质骨,已被证明具有高度遗传性;然而,关于调节小梁骨的特定遗传因素知之甚少。对914只来自C57BL/6J和C3H/HeJ近交系F2杂交的成年雌性小鼠的椎骨小梁骨特征进行全基因组连锁分析,揭示了一种源自13条常染色体的遗传调控模式,每个特征有5 - 13个数量性状基因座(QTL)。最终,鉴定调节小梁骨特征的基因可能会产生有关调节骨骼机械完整性机制的重要信息。
皮质骨和松质骨都影响骨骼的机械完整性,它们各自的相对贡献因骨骼部位而异。虽然反映皮质骨和松质骨的面积骨密度已被证明具有高度遗传性,但关于小梁骨密度和结构的遗传决定因素知之甚少。
为了鉴定椎骨小梁骨特征的遗传决定因素,我们评估了914只来自C57BL/6J(B6)和C3H/HeJ(C3H)亲本品系F2杂交的成年雌性小鼠的第五腰椎。使用高分辨率显微CT评估亲本品系(每个品系n = 8)和雌性B6C3H - F2后代(n = 914)椎体中小梁骨的总体积(TV)、骨体积(BV)、骨体积分数(BV/TV)、小梁厚度(Tb.Th)、间距(Tb.Sp)和数量(Tb.N)。对F2后代的基因组DNA进行筛选,以检测区分19条常染色体上B6和C3H等位基因的118个基于PCR的标记。
尽管C3H亲本品系的小梁骨腔略大,但与B6亲本品系相比,其椎体小梁骨BV/TV显著降低(-53%),Tb.N降低(-40%),Tb.Sp升高(71%)(所有p < 0.001)。全基因组数量性状分析揭示了一种源自13条常染色体的遗传调控模式,每个椎骨小梁骨特征有5 - 13个数量性状基因座(QTL),调整后的LOD分数范围为3.1至14.4。在调整其他QTL的贡献后,每个单独QTL在F2群体中解释的方差范围为0.8%至5.9%。总体而言,这些QTL解释了F2群体中椎体性状方差的22 - 33%。总之,我们使用C57BL/6J和C3H/HeJ近交小鼠品系的F2杂交观察到椎骨小梁骨体积分数和微结构的复杂遗传调控模式,并鉴定了一些QTL,其中一些与先前鉴定的总股骨和椎体BMD的QTL不同。鉴定调节小梁骨特征的基因最终可能会产生有关调节骨骼机械完整性的获得和维持机制的重要信息。