title: Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.
abstract: 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.
authors.affiliation: MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Karin E M
authors.initials: KE
authors.lastname: Diderich
authors.forename: Claudia
authors.initials: C
authors.lastname: Nicolaije
authors.forename: Matthias
authors.initials: M
authors.lastname: Priemel
authors.forename: Jan H
authors.initials: JH
authors.lastname: Waarsing
authors.forename: Judd S
authors.initials: JS
authors.lastname: Day
authors.forename: Renata M C
authors.initials: RM
authors.lastname: Brandt
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Schilling
authors.forename: Sander M
authors.initials: SM
authors.lastname: Botter
authors.forename: Harrie
authors.initials: H
authors.lastname: Weinans
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D000367:Age Factors; D019588:Aging, Premature / Q000235:genetics* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D004249:DNA Damage / Q000187:drug effects; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*
chemical_list: D010281:Parathyroid Hormone