Open AccessImpairment of osteoblast differentiation due to proliferation‐independent telomere dysfunction in mouse models of accelerated aging
Author(s) -
Wang Haitao,
Chen Qijun,
Lee SeoungHoon,
Choi Yongwon,
Brad Johnson Frederick,
Pignolo Robert J.
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2012.00838.x
Subject(s) - telomere , osteoblast , runx2 , biology , telomerase , cellular differentiation , microbiology and biotechnology , cancer research , progenitor cell , stem cell , genetics , gene , in vitro
Summary 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.