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

Karin E.M. Diderich, Claudia Nicolaije, Matthias Priemel, Jan H. Waarsing, Judd S. Day, Renata M.C. Brandt, Arndt F. Schilling, Sander M. Botter, Harrie Weinans, Gijsbertus T.J. Van Der Horst, Jan H.J. Hoeijmakers, Johannes P.T.M. Van Leeuwen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

18 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)845-861
Aantal pagina's17
Nummer van het tijdschrift4
StatusGepubliceerd - aug. 2012
Extern gepubliceerdJa


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