title: Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging.
abstract: We undertook genetic and nongenetic approaches to investigate the relationship between telomere maintenance and osteoblast differentiation, as well as to uncover a possible link between a known mediator of cellular aging and senile bone loss. Using mouse models of disrupted telomere maintenance molecules, including mutants in the Werner helicase (Wrn(-/-) ), telomerase (Terc(-/-) ), and Wrn(-/-)  Terc(-/-)  double mutants predisposed to accelerated bone loss, we measured telomere dysfunction-induced foci (TIFs) and markers of osteoblast differentiation in mesenchymal progenitor cells (MPCs). We found that telomere maintenance is directly and significantly related to osteoblast differentiation, with dysfunctional telomeres associated with impaired differentiation independent of proliferation state. Telomere-mediated defects in osteoblast differentiation are associated with increased p53/p21 expression and concomitant reduction in RUNX2. Conversely, MPCs from p53(-/-)  mice do not have substantial telomere dysfunction and spontaneously differentiate into osteoblasts. These results suggest that critical telomere dysfunction may be a prominent mechanism for age-related osteoporosis and limits MPC differentiation into bone-forming cells via the p53/p21 pathway.
authors.affiliation: Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.forename: Seoung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Frederick Brad
authors.initials: FB
authors.lastname: Johnson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
mesh_terms: D019588:Aging, Premature / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000201:enzymology / Q000473:pathology*; D010024:Osteoporosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D019098:Telomerase / Q000172:deficiency / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D019098:Telomerase; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse