Chronic alcohol abuse is the most important """"""""life style"""""""" risk factor for osteoporosis. The long-term goal of the proposed research is to understand the cellular and molecular mechanisms responsible for mediating alcohol's detrimental actions on the skeleton and, with this improved understanding, to develop effective countermeasures. Research performed during the current funding interval provides strong evidence that alcohol-induced bone loss is due to a disturbance in the bone remodeling cycle. Specifically, an imbalance in the coupling of bone formation to the prevailing rate of bone resorption creates inadequate new bone to compensate for bone resorption, resulting in net bone loss. At the molecular level, we have established a clear positive association between bone formation and insulin-like growth factor-I (IGF-1) gene expression in bone tissue. Furthermore, the architectural, cellular and gene expression changes in tibiae of rats fed alcohol are strikingly similar to those that follow hypophysectomy (HYPOX), suggesting that the underlying mechanisms for the skeletal response to alcohol abuse and growth hormone (GH) deficiency are similar. Because most of the effects of GH on bone cells are mediated by locally produced IGF-1, the detrimental skeletal effects of alcohol abuse and GH deficiency may share disturbed IGF-1 signaling as a common pathway. The antagonistic effects of HYPOX on bone formation can be reversed with parathyroid hormone (PTH), which up-regulates IGF-1 expression by bone cells. Based on these findings, our working hypotheses are that alcohol-induced osteoporosis is largely due to decreased IGF-1 expression by osteoblasts, and can be prevented or reversed by treatment with PTH. We propose to test these hypotheses in adult and adolescent female rat models for chronic alcohol abuse by determining changes in bone and mineral metabolism in: (1) HYPOX and intact rats fed alcohol; (2) HYPOX and intact rats fed alcohol and treated with GH; (3) HYPOX and intact rats fed alcohol and treated with IGF-1; and (4) HYPOX and intact rats simultaneously fed alcohol and treated with PTH; and (5) intact rats fed alcohol to induce bone loss and then treated with PTH. A suite of complementary techniques will be employed in these experiments to evaluate the skeletal changes, including dynamic and static bone histomorphometry, bone densitometry, micro-CT, biochemical markers, mechanical testing, immunohistochemistry, radioautography and RNA analysis by Northern blots and RNase protection assays.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011140-10
Application #
7046917
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Gentry, Thomas
Project Start
1996-09-29
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
10
Fiscal Year
2006
Total Cost
$310,894
Indirect Cost
Name
Oregon State University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Johnson, Teresa L; Gaddini, Gino; Branscum, Adam J et al. (2014) Effects of chronic heavy alcohol consumption and endurance exercise on cancellous and cortical bone microarchitecture in adult male rats. Alcohol Clin Exp Res 38:1365-72
Iwaniec, Urszula T; Turner, Russell T (2013) Intraperitoneal injection of ethanol results in drastic changes in bone metabolism not observed when ethanol is administered by oral gavage. Alcohol Clin Exp Res 37:1271-7
Marrone, Jill A; Maddalozzo, Gianni F; Branscum, Adam J et al. (2012) Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women. Menopause 19:974-9
Howe, K S; Iwaniec, U T; Turner, R T (2011) The effects of low dose parathyroid hormone on lumbar vertebrae in a rat model for chronic alcohol abuse. Osteoporos Int 22:1175-81
Iwaniec, Urszula T; Boghossian, Stéphane; Trevisiol, Cynthia H et al. (2011) Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. J Bone Miner Res 26:1506-16
Turner, Russell T; Iwaniec, Urszula T (2011) Low dose parathyroid hormone maintains normal bone formation in adult male rats during rapid weight loss. Bone 48:726-32
Turner, R T; Iwaniec, U T (2010) Moderate weight gain does not influence bone metabolism in skeletally mature female rats. Bone 47:631-5
Menagh, Philip J; Turner, Russell T; Jump, Donald B et al. (2010) Growth hormone regulates the balance between bone formation and bone marrow adiposity. J Bone Miner Res 25:757-68
Turner, Russell T; Rosen, Clifford J; Iwaniec, Urszula T (2010) Effects of alcohol on skeletal response to growth hormone in hypophysectomized rats. Bone 46:806-12
Maddalozzo, G F; Turner, R T; Edwards, C H T et al. (2009) Alcohol alters whole body composition, inhibits bone formation, and increases bone marrow adiposity in rats. Osteoporos Int 20:1529-38

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