Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis
Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis
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DOI：
10.1111/j.1474-9726.2007.00350.x
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发表时间：
2008-02-01
期刊：
影响因子：
7.8
通讯作者：
Johnson, F. Brad
中科院分区：
文献类型：
--
作者：
Pignolo, Robert J.;Suda, Robin K.;Johnson, F. Brad
骨质疏松症和相关的骨折风险是老年人面临的主要临床挑战。端粒在大多数人类组织（包括骨）中随着年龄的增长而缩短，并且由于端粒缩短是培养细胞（包括间充质干细胞（MSC）和成骨细胞）中细胞复制性衰老或凋亡的原因，因此假设端粒缩短有助于骨的老化。骨质疏松症常见于Werner综合征和先天性角化不良性早衰综合征，其特征是端粒功能障碍。端粒DNA是Escherichia coli解旋酶的靶点之一，但小鼠中较长的端粒和丰富的端粒酶使Escherichia coli在端粒处的需要最小化，因此Escherichia coli敲除小鼠相对健康。在一个加速衰老的模型中，将端粒酶（Terc）基因敲除小鼠的端粒缩短与突变相结合，导致增殖组织中的合成缺陷。在这里，我们证明，在BLORN（-/-）Terc（-/-）突变小鼠的缺陷导致低骨量表型，年龄相关性骨质疏松症是在完整的破骨细胞分化的背景下，成骨细胞分化受损的结果。此外，来自单突变小鼠和双突变小鼠的MSC具有减少的体外寿命，并且显示出受损的成骨潜力，伴随着过早衰老的特征。这些结果为成骨细胞前体细胞的复制性老化是老年性骨质疏松的重要机制提供了证据。
Osteoporosis and the associated risk of fracture are major clinical challenges in the elderly. Telomeres shorten with age in most human tissues, including bone, and because telomere shortening is a cause of cellular replicative senescence or apoptosis in cultured cells, including mesenchymal stem cells (MSCs) and osteoblasts, it is hypothesized that telomere shortening contributes to the aging of bone. Osteoporosis is common in the Werner (Wrn) and dyskeratosis congenita premature aging syndromes, which are characterized by telomere dysfunction. One of the targets of the Wrn helicase is telomeric DNA, but the long telomeres and abundant telomerase in mice minimize the need for Wrn at telomeres, and thus Wrn knockout mice are relatively healthy. In a model of accelerated aging that combines the Wrn mutation with the shortened telomeres of telomerase (Terc) knockout mice, synthetic defects in proliferative tissues result. Here, we demonstrate that deficiencies in Wrn(-/-) Terc(-/-) mutant mice cause a low bone mass phenotype, and that age-related osteoporosis is the result of impaired osteoblast differentiation in the context of intact osteoclast differentiation. Further, MSCs from single and Wrn(-/-) Terc(-/-) double mutant mice have a reduced in vitro lifespan and display impaired osteogenic potential concomitant with characteristics of premature senescence. These data provide evidence that replicative aging of osteoblast precursors is an important mechanism of senile osteoporosis.