Impairment of osteoblast differentiation due to proliferation‐independent telomere dysfunction in mouse models of accelerated aging
Open accessAbstract
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.
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Late-generation telomerase-deficient mice recapitulate features of osteoporosis including decreased bone volume, diminished osteoblast number and function, and increased porosity.
“late-generation telomerase-deficient mice recapitulate several features of osteoporosis, such as decreased bone volume, diminished osteoblast number and function, and increased porosity”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [132]
The Introduction reports low bone mass in older telomerase-deficient mice, and the Results report reduced osteoblast differentiation in fourth-generation Terc−/− mice compared with first-generation mice. The paper does not report increased bone porosity or a diminished in-vivo osteoblast count in late-generation mice; its cell-count measures concern mesenchymal progenitors and osteoblast-forming colonies. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTAFs are associated with impaired osteoblast differentiation.
“with TAFs being associated with impaired osteoblast differentiation132,133”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [132]
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Telomere dysfunction in ageing and age-related diseases
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Self-citation
- Authors
- Wang, H., Chen, Q., Lee, S., Choi, Y., Brad Johnson, F., & Pignolo, R. J.
- Affiliations
- University of Pennsylvania (US)
- Wonkwang University (KR)
- Corresponding author
- Pignolo, Robert J.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-06-11
- Volume
- 11
- Issue
- 4
- Pages
- 704-713
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3400025
- OpenAlex
- W1722531939
- Cited by
- 81
- References
- 43
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute on Aging (R01AG021521, R01AG028873)
- Penn Center for Musculoskeletal Disorders
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomere dysfunction, osteogenic differentiation, accelerated aging, Werner syndrome, telomerase, mesenchymal progenitor cells, p53/p21 pathway, Runx2, senile osteoporosis, telomere maintenance
- MeSH terms
- Werner Syndrome Helicase, Animals, Cell Differentiation, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Osteoblasts, Osteoporosis, Signal Transduction, Cellular Senescence, Mice, Knockout, Telomerase, Aging, Premature, Mice, RecQ Helicases, Telomere Homeostasis, Mesenchymal Stem Cells
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