Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.
Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.
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DOI：
10.1007/s11357-011-9291-8
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
van Leeuwen JP
中科院分区：
文献类型：
--
作者：
Diderich KE;Nicolaije C;Priemel M;Waarsing JH;Day JS;Brandt RM;Schilling AF;Botter SM;Weinans H;van der Horst GT;Hoeijmakers JH;van Leeuwen JP
毛发硫营养不良（TTD）是一种罕见的常染色体隐性核苷酸切除修复（NER）疾病，由双重功能NER/基础转录因子TFIIH的组分突变引起。TTD小鼠在Xpd基因中携带基于患者的点突变，与人类综合征的许多特征惊人地相似，并表现出过早衰老的迹象。为了研究TTD小鼠在多大程度上类似于正常的衰老过程，我们彻底研究了骨表型。在这里，我们表明，雌性TTD小鼠表现出加速骨老化从39周起，以及缺乏骨膜附着导致骨强度降低。在39周之前，野生型和TTD小鼠的骨骼是相同的，除了发育缺陷。尽管骨形成减少，但TTD小鼠中的成骨细胞保留了骨形成能力，因为体内PTH治疗导致皮质厚度增加。体外骨髓细胞培养表明，TTD骨祖细胞保留分化成成骨细胞的能力。然而，13周龄后，TTD雌性显示骨结节形成减少。未检测到骨吸收或破骨细胞数量增加。总之，TTD小鼠表现出过早的骨老化，这是由间充质干细胞/骨祖细胞的减少和全身因素的变化，确定DNA损伤和修复作为骨脆性的关键决定因素，通过影响骨生成和骨代谢。
Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism.
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影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
4
作者：
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EGLY, JM
影响因子：
4.1
作者：
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通讯作者：
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影响因子：
16
作者：
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通讯作者：
Weeda, G
影响因子：
4
作者：
Hoeijmakers, JHJ;Egly, JM;Vermeulen, W
通讯作者：
Vermeulen, W