Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis.
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.
Pignolo
Robert J
RJ
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. pignolo@mail.med.upenn.edu
Suda
Robin K
RK
McMillan
Emily A
EA
Shen
Johnny
J
Lee
Seoung-Hoon
SH
Choi
Yongwon
Y
Wright
Alexander C
AC
Johnson
F Brad
FB
D000375:Aging; D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D059630:Mesenchymal Stem Cells; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D053484:RecQ Helicases / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
D019098:Telomerase; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse