Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice

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.

Subjects

DNA repair syndromes

Mouse models

Aging

Bone strength

Bone fragility

Bone marrow stem cells

DDC Class

610: Medizin

Funding Organisations

European Commission

Netherlands Organization for Scientific Research (NWO)

Research Institute Diseases of the Elderly

Dutch Cancer Society

More Funding Information

This research was supported in part by the Netherlands Organization for Scientific Research (NWO) through the foundation of the Research Institute Diseases of the Elderly, as well as grants from NIH (1PO1 AG17242-02), NIEHS (1UO1 ES011044), EC (QRTL-1999-02002), the Dutch Cancer Society (EUR 99–2004) and the European Commission (EU-LSHG-CT-2007-036894 ‘LifeSpan’).

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http://rightsstatements.org/vocab/InC/1.0/

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Diderich2012_Article_BoneFragilityAndDeclineInStemC.pdf

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Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice