Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.
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Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice. / Diderich, Karin E M; Nicolaije, Claudia; Priemel, Matthias; Waarsing, Jan H; Day, Judd S; Brandt, Renata M C; Schilling, Arndt; Botter, Sander M; Weinans, Harrie; Horst, van der; Gijsbertus, T J; Hoeijmakers, Jan H J; Leeuwen, van; Johannes, P T M.
in: AGE (DORDR), Jahrgang 34, Nr. 4, 4, 2012, S. 845-861.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.
AU - Diderich, Karin E M
AU - Nicolaije, Claudia
AU - Priemel, Matthias
AU - Waarsing, Jan H
AU - Day, Judd S
AU - Brandt, Renata M C
AU - Schilling, Arndt
AU - Botter, Sander M
AU - Weinans, Harrie
AU - Horst, van der
AU - Gijsbertus, T J
AU - Hoeijmakers, Jan H J
AU - Leeuwen, van
AU - Johannes, P T M
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Female
KW - Age Factors
KW - Sensitivity and Specificity
KW - Immunohistochemistry
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred C57BL
KW - Microscopy, Electron
KW - Analysis of Variance
KW - Reference Values
KW - Random Allocation
KW - Osteogenesis/drug effects/genetics
KW - Osteoblasts/metabolism
KW - Osteoclasts/metabolism
KW - Aging, Premature/genetics/physiopathology
KW - Bone and Bones/drug effects/pathology/ultrastructure
KW - DNA Damage/drug effects
KW - DNA Repair-Deficiency Disorders/genetics
KW - Hematopoietic Stem Cells/metabolism
KW - Osteoporosis/genetics/physiopathology
KW - Parathyroid Hormone/pharmacology
KW - Trichothiodystrophy Syndromes/genetics
KW - Animals
KW - Female
KW - Age Factors
KW - Sensitivity and Specificity
KW - Immunohistochemistry
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred C57BL
KW - Microscopy, Electron
KW - Analysis of Variance
KW - Reference Values
KW - Random Allocation
KW - Osteogenesis/drug effects/genetics
KW - Osteoblasts/metabolism
KW - Osteoclasts/metabolism
KW - Aging, Premature/genetics/physiopathology
KW - Bone and Bones/drug effects/pathology/ultrastructure
KW - DNA Damage/drug effects
KW - DNA Repair-Deficiency Disorders/genetics
KW - Hematopoietic Stem Cells/metabolism
KW - Osteoporosis/genetics/physiopathology
KW - Parathyroid Hormone/pharmacology
KW - Trichothiodystrophy Syndromes/genetics
M3 - SCORING: Journal article
VL - 34
SP - 845
EP - 861
JO - AGE (DORDR)
JF - AGE (DORDR)
SN - 0161-9152
IS - 4
M1 - 4
ER -
