» Articles » PMID: 22506075

Age-related Skeletal Dynamics and Decrease in Bone Strength in DNA Repair Deficient Male Trichothiodystrophy Mice

Abstract

Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.

Citing Articles

Cellular senescence and the skeleton: pathophysiology and therapeutic implications.

Khosla S, Farr J, Monroe D J Clin Invest. 2022; 132(3).

PMID: 35104801 PMC: 8803328. DOI: 10.1172/JCI154888.


DNA damage in aging, the stem cell perspective.

McNeely T, Leone M, Yanai H, Beerman I Hum Genet. 2019; 139(3):309-331.

PMID: 31324975 PMC: 6980431. DOI: 10.1007/s00439-019-02047-z.


DNA repair fidelity in stem cell maintenance, health, and disease.

Mani C, Reddy P, Palle K Biochim Biophys Acta Mol Basis Dis. 2019; 1866(4):165444.

PMID: 30953688 PMC: 6935429. DOI: 10.1016/j.bbadis.2019.03.017.


The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging.

Farr J, Almeida M J Bone Miner Res. 2018; 33(9):1568-1584.

PMID: 30075061 PMC: 6327947. DOI: 10.1002/jbmr.3564.


Time series clustering of mRNA and lncRNA expression during osteogenic differentiation of periodontal ligament stem cells.

Zheng Y, Li X, Huang Y, Jia L, Li W PeerJ. 2018; 6:e5214.

PMID: 30038865 PMC: 6052852. DOI: 10.7717/peerj.5214.


References
1.
Hanawalt P . Subpathways of nucleotide excision repair and their regulation. Oncogene. 2002; 21(58):8949-56. DOI: 10.1038/sj.onc.1206096. View

2.
BOOTSMA D, Hoeijmakers J . DNA repair. Engagement with transcription. Nature. 1993; 363(6425):114-5. DOI: 10.1038/363114a0. View

3.
Itin P, Sarasin A, Pittelkow M . Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol. 2001; 44(6):891-920; quiz 921-4. DOI: 10.1067/mjd.2001.114294. View

4.
Wijnhoven S, Beems R, Roodbergen M, van den Berg J, Lohman P, Diderich K . Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction. DNA Repair (Amst). 2005; 4(11):1314-24. DOI: 10.1016/j.dnarep.2005.07.002. View

5.
Diderich K, Nicolaije C, Priemel M, Waarsing J, Day J, Brandt R . Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice. Age (Dordr). 2011; 34(4):845-61. PMC: 3682057. DOI: 10.1007/s11357-011-9291-8. View