Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis

Tracy A. Brennan, Kevin P. Egan, Carter M. Lindborg, Qijun Chen, Mariya T. Sweetwyne, Kurt D. Hankenson, Sharon X. Xie, Frederick B. Johnson, Robert Pignolo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn-/-), telomerase (Terc-/-) and Wrn-/-Terc-/- double mutants. Compared with young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc-/- and Wrn-/-Terc-/- mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc-/- and Wrn-/-Terc-/- mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc-/- and Wrn -/-Terc-/- mice compared with older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc-/- and Wrn-/-Terc-/- bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn-/- single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy and moment of inertia) of the Terc-/- and Wrn-/-Terc-/- femurs compared with WT mice were also observed. Young Wrn-/-Terc-/- mice had a statistically significant increase in bone-marrow fat content compared with young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc-/- and Wrn-/-Terc -/- mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.

Original languageEnglish (US)
Pages (from-to)583-592
Number of pages10
JournalDMM Disease Models and Mechanisms
Volume7
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Telomere
Osteoporosis
Bone
Osteoblasts
Aging of materials
Bone and Bones
Telomere Shortening
Computerized tomography
Telomerase
Genotype
Werner Syndrome
Model structures
Phenotype
Minerals
Cell Aging
Porosity
Osteoclasts
Fats
Osteogenesis
Femur

Keywords

  • Aging
  • Bone histomorphometry
  • Osteoporosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)
  • Medicine(all)

Cite this

Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. / Brennan, Tracy A.; Egan, Kevin P.; Lindborg, Carter M.; Chen, Qijun; Sweetwyne, Mariya T.; Hankenson, Kurt D.; Xie, Sharon X.; Johnson, Frederick B.; Pignolo, Robert.

In: DMM Disease Models and Mechanisms, Vol. 7, No. 5, 01.01.2014, p. 583-592.

Research output: Contribution to journalArticle

Brennan, TA, Egan, KP, Lindborg, CM, Chen, Q, Sweetwyne, MT, Hankenson, KD, Xie, SX, Johnson, FB & Pignolo, R 2014, 'Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis', DMM Disease Models and Mechanisms, vol. 7, no. 5, pp. 583-592. https://doi.org/10.1242/dmm.014928
Brennan, Tracy A. ; Egan, Kevin P. ; Lindborg, Carter M. ; Chen, Qijun ; Sweetwyne, Mariya T. ; Hankenson, Kurt D. ; Xie, Sharon X. ; Johnson, Frederick B. ; Pignolo, Robert. / Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. In: DMM Disease Models and Mechanisms. 2014 ; Vol. 7, No. 5. pp. 583-592.
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