Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis

Robert J. Pignolo, Robin K. Suda, Emily A. Mcmillan, Johnny Shen, Seoung Hoon Lee, Yongwon Choi, Alexander C. Wright, F. Brad Johnson

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Osteoporosis and the associated risk of fracture are major clinical challenges in the elderly. Telomeres shorten with age in most human tissues, including bone, and because telomere shortening is a cause of cellular replicative senescence or apoptosis in cultured cells, including mesenchymal stem cells (MSCs) and osteoblasts, it is hypothesized that telomere shortening contributes to the aging of bone. Osteoporosis is common in the Werner (Wrn) and dyskeratosis congenita premature aging syndromes, which are characterized by telomere dysfunction. One of the targets of the Wrn helicase is telomeric DNA, but the long telomeres and abundant telomerase in mice minimize the need for Wrn at telomeres, and thus Wrn knockout mice are relatively healthy. In a model of accelerated aging that combines the Wrn mutation with the shortened telomeres of telomerase (Terc) knockout mice, synthetic defects in proliferative tissues result. Here, we demonstrate that deficiencies in Wrn-/-Terc-/- mutant mice cause a low bone mass phenotype, and that age-related osteoporosis is the result of impaired osteoblast differentiation in the context of intact osteoclast differentiation. Further, MSCs from single and Wrn-/-Terc-/- double mutant mice have a reduced in vitro lifespan and display impaired osteogenic potential concomitant with characteristics of premature senescence. These data provide evidence that replicative aging of osteoblast precursors is an important mechanism of senile osteoporosis.

Original languageEnglish (US)
Pages (from-to)23-31
Number of pages9
JournalAging Cell
Issue number1
StatePublished - Feb 2008


  • Aging
  • Dyskeratosis congenita
  • Osteoblast differentiation
  • Osteoporosis
  • Telomerase
  • Werner syndrome

ASJC Scopus subject areas

  • Aging
  • Cell Biology


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