This project seeks to identify the ways in which changes in the cells of adult human bone marrow contribute to skeletal aging. The effects of aging on osteoblast differentiation from the human bone marrow stromal cell compartment are of importance for understanding the mechanisms and treatment of age-related bone loss and osteoporosis. Previously, we found in both two-dimensional (2D) and in three-dimensional (3D) model systems that adherent human bone marrow stromal cells (hMSCs) undergo an age-dependent decrease in capacity for differentiation to alkaline phosphatase-positive (AlkP+) cells. The first specific aim tests the hypotheses that the STRO-1-positive (+) fraction of marrow stromal cells is decreased in frequency with age and that there a decrease in differentiation to AlkP+ pre-osteoblasts and decrease in 3D bone formation in vitro. These decreases are likely to be associated with an increase in adipocyte differentiation. Methods include immuno-sorting and quantitative molecular methods to characterize the osteoblast and adipocyte lineages. The second specific aim tests the hypotheses that with aging, there is diminished signal transduction in response to osteo-anabolic agents like parathyroid hormone (PTH) and sex hormones and the third specific aim tests whether combination treatments may reverse the age-specific decrease in bone marrow stromal cell differentiation to osteoblasts. The mechanism of enhancement will be assessed, with focus on regulation of IGF-1 and on apoptosis. Age-related dysfunction in signaling and regulatory mediators will be examined. We shall determine whether there is consistency is the age-related decline in PTH signaling in hMSCs, whether this involves CREB 1 and 2 pathways, whether specific chemical inhibitors and/or CREB knockdown by siRNA technology reduce PTH signaling in hMSCs from young individuals and thus decrease IGF-I and osteoblastogenesis to levels found in elder hMSCs. This research will quantify osteoblastogenesis and bone formation by marrow cells from young and old subjects. These studies should provide valuable information on the age-dependent changes in bone marrow stromal cells, provide insights into novel strategies for rejuvenation of cellular physiology leading to improved osteogenesis, and begin to reveal mechanisms whereby these agents can promote osteoblast differentiation in cells from aged individuals. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028114-02
Application #
7390355
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Williams, John
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$281,260
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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