Analysis of osteoarthritis in a mouse model of the progeroid human DNA repair syndrome trichothiodystrophy.
The increasing average age in developed societies is paralleled by an increase in the prevalence of many age-related diseases such as osteoarthritis (OA), which is characterized by deformation of the joint due to cartilage damage and increased turnover of subchondral bone. Consequently, deficiency in DNA repair, often associated with premature aging, may lead to increased pathology of these two tissues. To examine this possibility, we analyzed the bone and cartilage phenotype of male and female knee joints derived from 52- to 104-week-old WT C57Bl/6 and trichothiodystrophy (TTD) mice, who carry a defect in the nucleotide excision repair pathway and display many features of premature aging. Using micro-CT, we found bone loss in all groups of 104-week-old compared to 52-week-old mice. Cartilage damage was mild to moderate in all mice. Surprisingly, female TTD mice had less cartilage damage, proteoglycan depletion, and osteophytosis compared to WT controls. OA severity in males did not significantly differ between genotypes, although TTD males had less osteophytosis. These results indicate that in premature aging TTD mice age-related changes in cartilage were not more severe compared to WT mice, in striking contrast with bone and many other tissues. This segmental aging character may be explained by a difference in vasculature and thereby oxygen load in cartilage and bone. Alternatively, a difference in impact of an anti-aging response, previously found to be triggered by accumulation of DNA damage, might help explain why female mice were protected from cartilage damage. These findings underline the exceptional segmental nature of progeroid conditions and provide an explanation for pro- and anti-aging features occurring in the same individual.
Botter
Sander M
SM
Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Zar
Michel
M
van Osch
Gerjo J V M
GJ
van Steeg
Harry
H
Dollé
Martijn E T
ME
Hoeijmakers
Jan H J
JH
Weinans
Harrie
H
van Leeuwen
Johannes P T M
JP
D019588:Aging, Premature / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001847:Bone Diseases / Q000175:diagnosis; D002357:Cartilage Diseases / Q000175:diagnosis; D004260:DNA Repair; D004195:Disease Models, Animal; D005260:Female; D007719:Knee Joint / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000175:diagnosis / Q000503:physiopathology*; D013977:Tibia / Q000473:pathology*; D054463:Trichothiodystrophy Syndromes / Q000503:physiopathology*; D055114:X-Ray Microtomography
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