This application addresses two of the goals of the RFA: Use """"""""of in vitro methods to assay stem cell function that reflect individual differences among cell or tissue donors"""""""" and """"""""Potential systemic effects of age-related alterations in stem and precursor cell properties in specific lineages."""""""" Skeletal aging is characterized as a gradual loss of bone mass due to an excess of bone resorption that is not balanced by new bone formation. Thus, with age, there is a gradual loss of bone measured by declining bone mineral density (BMD), to the point of osteopenia or osteoporosis, and bone fracture. Bone marrow becomes fatty and ultimately """"""""gelatinized"""""""" with extreme age and osteoporosis. In addition, elderly people commonly have lower circulating levels of 25-dihydroxyvitamin D (25-D). Marrow stromal cells (MSCs) give rise to osteoblasts, but there is some discrepancy in the literature about the effect of age on osteoblast differentiation. We, and others, reported that there is an age-related decline in osteoblastogenesis from human bone marrow. Some others, using colony assays, report no detectable change. We have been applying an innovative automated cell tracking system developed by Dr. Greenberger for hematopoietic cells for research in skeletal aging. We have extensive experience with human marrow obtained from subjects undergoing total hip replacement for non-inflammatory joint disease. We have developed a research plan with 3 specific aims to test the hypotheses 1) that with aging there is a loss of osteoblast potential in human marrow stromal cells from men and women; 2) that vitamin D-deficiency reduces osteoblast potential, and 3) that cells from elders and vitamin D-deficient subjects can be rejuvenated in vitro by vitamin D metabolites or analogs. We will use biochemical and molecular methods to enumerate and characterize MSCs with osteoblast potential. We propose to use an innovative quantitative cell tracking system to measure differentiation as a function of age of human marrow. We will also use monolayer culture methods to assess the effects of age on progress in osteoblast differentiation. We will determine whether vitamin D metabolites or analogs promote osteoblast differentiation of marrow cells and whether the mechanisms involve increasing numbers of progenitors, changes in proliferation and apoptosis, and/or stimulation of osteoblast differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025015-03
Application #
7096667
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
Program Officer
Dutta, Chhanda
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$388,484
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Chung, Ping-Lin; Zhou, Shuanhu; Eslami, Behnam et al. (2014) Effect of age on regulation of human osteoclast differentiation. J Cell Biochem 115:1412-9
Geng, Shuo; Zhou, Shuanhu; Bi, Zhenggang et al. (2013) Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells. Metabolism 62:768-77
Zhou, Shuanhu; Geng, Shuo; Glowacki, Julie (2013) Histone deacetylation mediates the rejuvenation of osteoblastogenesis by the combination of 25(OH)D3 and parathyroid hormone in MSCs from elders. J Steroid Biochem Mol Biol 136:156-9
Zhou, Shuanhu; Leboff, Meryl S; Waikar, Sushrut S et al. (2013) Vitamin D metabolism and action in human marrow stromal cells: effects of chronic kidney disease. J Steroid Biochem Mol Biol 136:342-4
Zhou, Shuanhu; Glowacki, Julie; Kim, Sung Won et al. (2012) Clinical characteristics influence in vitro action of 1,25-dihydroxyvitamin D(3) in human marrow stromal cells. J Bone Miner Res 27:1992-2000
Zhou, Shuanhu (2011) TGF-? regulates ?-catenin signaling and osteoblast differentiation in human mesenchymal stem cells. J Cell Biochem 112:1651-60
Shen, Longxiang; Glowacki, Julie; Zhou, Shuanhu (2011) Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells. Exp Cell Res 317:1796-803
Eslami, Behnam; Zhou, Shuanhu; Van Eekeren, Inge et al. (2011) Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate. Calcif Tissue Int 88:272-80
Geng, Shuo; Zhou, Shuanhu; Glowacki, Julie (2011) Effects of 25-hydroxyvitamin D(3) on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1?-hydroxylase. J Bone Miner Res 26:1145-53
Zhou, Shuanhu; Bueno, Ericka M; Kim, Sung Won et al. (2011) Effects of age on parathyroid hormone signaling in human marrow stromal cells. Aging Cell 10:780-8

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