Szumska Dorota, Benes Helen, Kang Ping, Weinstein Robert S, Jilka Robert L, Manolagas Stavros C, Shmookler Reis Robert J
Department of Geriatrics, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.
Bone. 2007 Mar;40(3):758-66. doi: 10.1016/j.bone.2006.10.012. Epub 2006 Dec 19.
Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F(2) progeny of an AKR/JxSAMP6 cross, at 4 months of age, the BMD variance was 5-6% of the mean, vs. 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed DeltasBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R=-0.23) or body weight (R=-0.12) at maturity. Heritability of the DeltasBMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity--implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F(2) populations (P<10(-4) for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women [Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, et al. Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Hum Mol Genet 2005;14:3141-8]. A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.
对两种小鼠品系AKR/J和SAMP6的脊柱骨密度进行了纵向评估。它们表现出非常不同的骨累积时间进程，SAMP6品系在3个月时脊柱骨密度达到平台期，而AKR/J小鼠的脊柱骨密度至少持续增加8个月。在AKR/J×SAMP6杂交的253只F(2)后代中，4月龄时，骨密度方差为平均值的5 - 6%，而体重方差为15%。所测量的每个参数的方差均随年龄增加，且在雄性中通常更高。6月龄/4月龄脊柱骨密度的比值（称为ΔsBMD）呈正态分布，方差为5.7%，并且在成熟时很大程度上独立于脊柱骨密度（R = -0.23）或体重（R = -0.12）。计算得出ΔsBMD性状的遗传力为0.59。基因定位确定了两个显著位点，均与成熟时骨密度所观察到的位点不同——这意味着不同的基因调控骨骼生长与重塑。X染色体上的一个位点在两个小鼠F(2)群体中得到重复验证（联合发现和验证的P<10(-4)），影响脊柱和整个骨骼的年龄依赖性骨密度变化。其位置与通过关联定位确定的一个非常狭窄的区域一致，该区域对绝经后女性腰椎骨密度有影响[帕森斯CA，姆罗茨科夫斯基HJ，麦奎根FE, 阿尔巴加OM, 马诺拉加斯S, 里德DM等。种间同线性定位确定人类Xp22染色体上骨密度的数量性状位点。《人类分子遗传学》2005；14：3141 - 8]。在仅一次杂交中观察到位于7号染色体上的第二个位点。单核苷酸多态性（SNP）在这些位点附近高度聚集，仅在有限范围内区分亲本品系。
