A fundamental aspect of age-related bone loss is the decreased proliferative capacity and impaired differentiation of osteoblasts in the bone of older individuals. Telomeres shorten with age in most human tissues, including bone, and since telomere shortening is a cause of cellular replicative senescence in cultured cells, including osteoblasts and mesenchymal stem cells (MSCs), it is likely that telomere status in MSCs is a critical component of bone formation. Osteoporosis is common in the Werner (Wrn) and Dyskeratosis congenita (DC) premature aging syndromes. 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 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, including bone, have been observed. It is hypothesized that deficiencies in genome maintenance molecules such as TERC and WRN cause a low bone mass phenotype and microarchitectural abnormalities of bone by impairing the ability of MSCs to differentiate into osteoblasts. It is further hypothesized that effective osteoblast differentiation depends on the presence of functional MSCs and hematopoietic stem cells (HSCs). Using micro-CT analysis and bone histomorphometry, this proposal will establish the relationship between the WRN and TERC molecules and structural bone fidelity, including microarchitecture and bone density. We will determine if age-related bone abnormalities in Wrn-/-, Terc-/- and Wrn -/- Terc-/- mice are related to deficiencies in osteoblast differentiation and/or increased osteoclastogenic potential, and will examine whether anabolic defects due to MSC impairment in mutant mice are associated with replicative senescence and/or telomere shortening/uncapping. We will also assess the contributions of MSCs and HSCs to osteoblast differentiation by selective and nonselective bone marrow transplantation of these cellular progenitors and analysis of their ability to reduce age-related osteoporotic changes. A consequence and major clinical challenge in the elderly is osteoporosis and associated high risk of fracture. The Wrn-/-Terc -/- mutant mouse recapitulates senile osteoporosis characterized by decreased bone-forming capacity and provides a system to test stem cell replacement for amelioration of age-related osteoporosis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Williams, John
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Farr, Joshua N; Fraser, Daniel G; Wang, Haitao et al. (2016) Identification of Senescent Cells in the Bone Microenvironment. J Bone Miner Res 31:1920-1929
Singh, Lakshman; Brennan, Tracy A; Russell, Elizabeth et al. (2016) Aging alters bone-fat reciprocity by shifting in vivo mesenchymal precursor cell fate towards an adipogenic lineage. Bone 85:29-36
Ko, Kang I; Coimbra, Leila S; Tian, Chen et al. (2015) Diabetes reduces mesenchymal stem cells in fracture healing through a TNF?-mediated mechanism. Diabetologia 58:633-642
Coimbra, L S; Steffens, J P; Alsadun, S et al. (2015) Clopidogrel Enhances Mesenchymal Stem Cell Proliferation Following Periodontitis. J Dent Res 94:1691-7
Lindborg, Carter M; Propert, Kathleen J; Pignolo, Robert J (2015) Conservation of pro-longevity genes among mammals. Mech Ageing Dev 146-148:23-7
Brennan, Tracy A; Egan, Kevin P; Lindborg, Carter M et al. (2014) Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. Dis Model Mech 7:583-92
Singh, Lakshman; Brennan, Tracy A; Kim, Jung-Hoon et al. (2013) Long-term functional engraftment of mesenchymal progenitor cells in a mouse model of accelerated aging. Stem Cells 31:607-11
Wang, Haitao; Brennan, Tracy A; Russell, Elizabeth et al. (2013) R-Spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis. J Mol Med (Berl) 91:1421-9
Wang, Haitao; Chen, Qijun; Lee, Seoung-Hoon et al. (2012) Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell 11:704-13
Egan, Kevin P; Brennan, Tracy A; Pignolo, Robert J (2012) Bone histomorphometry using free and commonly available software. Histopathology 61:1168-73

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