Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis.
Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis.
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DOI：
10.1242/dmm.014928
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发表时间：
2014-05
影响因子：
4.3
通讯作者：
Pignolo RJ
中科院分区：
文献类型：
--
作者：
Brennan TA;Egan KP;Lindborg CM;Chen Q;Sweetwyne MT;Hankenson KD;Xie SX;Johnson FB;Pignolo RJ
老年人面临的一个主要医疗挑战是骨质疏松症和骨折的高风险。端粒功能障碍是细胞衰老和端粒缩短的原因，其随着年龄的增长发生在大多数人体组织（包括骨）的细胞中。端粒缺陷导致两种以过早骨质疏松为特征的早老性疾病，即Werner综合征和先天性角化不良。据推测，端粒缩短有助于骨老化。我们评估了具有破坏的端粒维持机制的小鼠的骨骼表型作为人类骨老化的模型，包括Werner解旋酶（Werner-/-），端粒酶（Terc-/-）和Werner-/-Terc-/-双突变体的突变体。与年轻的野生型（WT）小鼠相比，微型计算机断层扫描分析显示，年轻的Terc−/−和Tern −/−Terc−/−小鼠的骨小梁体积、骨小梁数量和骨小梁厚度减少，骨小梁间距增加。在皮质骨中，相对于年龄匹配的WT小鼠，年轻的Terc−/−和Baun −/−Terc−/−小鼠的皮质变薄程度增加，孔隙率增加。与年龄较大的WT小鼠相比，Terc−/−和Tern −/−Terc−/−小鼠的这些骨小梁和皮质变化随着年龄的增长而加速。老年小鼠成骨细胞的组织学定量显示，所有基因型的成骨细胞数量相似;然而，老年Terc−/−骨和老年Terc −/−骨的类骨质、矿化表面、矿物质沉积率和骨形成率显著降低，表明成骨细胞功能障碍是这些小鼠早熟衰老的一个突出特征。除了在α n −/−单突变体中，破骨细胞数量在任何基因型中都没有增加。与WT小鼠相比，还观察到Terc−/−和Tern −/−Terc−/−股骨的力学参数（结构模型指数、各向异性程度和惯性矩）发生显著变化。与年轻的WT小鼠相比，年轻的BRN-/-Terc-/-小鼠的骨髓脂肪含量在统计学上显著增加，而老年的双突变体小鼠的骨髓脂肪含量仍然升高。综上所述，我们的研究结果表明，Terc−/−和Tern −/−Terc−/−突变体概括了人类骨老化表型，是研究年龄相关性骨质疏松症的有用模型。
A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn−/−), telomerase (Terc−/−) and Wrn−/−Terc−/− double mutants. Compared with young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc−/− and Wrn−/−Terc−/− mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc−/− and Wrn−/−Terc−/− mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc−/− and Wrn−/−Terc−/− mice compared with older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc−/− and Wrn−/−Terc−/− bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn−/− single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy and moment of inertia) of the Terc−/− and Wrn−/−Terc−/− femurs compared with WT mice were also observed. Young Wrn−/−Terc−/− mice had a statistically significant increase in bone-marrow fat content compared with young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc−/− and Wrn−/−Terc−/− mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.
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影响因子：
2.8
作者：
Chen H;Zhou X;Fujita H;Onozuka M;Kubo KY
通讯作者：
Kubo KY
影响因子：
4.1
作者：
Ding, M;Hvid, I
通讯作者：
Hvid, I
DOI：
10.1073/pnas.1036475100
发表时间：
2003-05-13
影响因子：
11.1
作者：
Bonyadi, M;Waldman, SD;Stanford, WL
通讯作者：
Stanford, WL
影响因子：
3.3
作者：
Jiang, YB;Zhao, J;Genant, HK
通讯作者：
Genant, HK
影响因子：
15.9
作者：
Kawaguchi, H;Manabe, N;Kuro-o, M
通讯作者：
Kuro-o, M