Disuse causes osteolysis of the skeleton, with attendant hypercalcemia, hypercalciuria and osteoporosis. Immobilization with a cast and stress shielding by an orthopedic implant result in localized bone loss. Although these problems have been recognized for decades, there has been limited progress towards identifying the underlying cellular and biochemical changes. Consequently, at present, there is no effective treatment to prevent bone wasting associated with disuse. Previous studies in man and animals have emphasized the role of increased bone resorption in development of disuse osteopenia. However, the results of studies that we carried out in the previous grant period indicate that decreased bone formation may account for most of the deficit. These findings suggest to us that osteoblast activity is modulated by gravitational loading and muscle loading. The hypothesis of this proposal that osteoblasts are under direct regulation of mechanical loading at the level of gene expression will be tested in rats subjected to the near weightlessness of orbital spaceflight and unweighting due to hind limb suspension. We postulate that weight bearing modulates the elaboration of specific signaling molecules (growth factors) by osteoblasts and, in turn, these signaling molecules promote normal coupling of bone formation and bone resorption. Normal coupling is essential to maintenance of bone volume: it is the pronounced uncoupling that occurs during disuse which leads to potentially catastrophic bone loss in humans. Although several signaling molecules may be involved, the weight of evidence favors transforming growth factor-beta (TGF-beta) as having an important role in this process. TGF-beta is produced by osteoblasts, acts on osteoblasts and osteoclasts, is incorporated into bone matrix and its secretion may be altered by weight bearing. The proposed studies will challenge this postulated role of TGF-beta in modulating the skeletal effects of weight bearing by 1) determining the magnitude of changes in bone resorption following disuse and reloading, 2) determining the effects of disuse and reloading on TGF-beta expression in bone cells, 3) determining the effects of disuse and reloading on mRNA levels for bone matrix proteins, 4) localizing TGF-beta mRNA and peptide in skeletal tissues at the cellular level, and 5) establishing whether locally administered TGF-P counteracts the effects of disuse on bone matrix synthesis and bone resorption. If the proposed hypothesis is correct, it may be possible to prevent disuse osteopenia by manipulating the levels of specific signaling molecules in the unweighted skeleton.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR035651-07
Application #
3157317
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1984-12-01
Project End
1996-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Gill, R K; Turner, R T; Wronski, T J et al. (1998) Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor beta in rat bone, and reduction is prevented by testosterone. Endocrinology 139:546-50
Evans, G L; Morey-Holton, E; Turner, R T (1998) Spaceflight has compartment- and gene-specific effects on mRNA levels for bone matrix proteins in rat femur. J Appl Physiol 84:2132-7
Zhang, M; Turner, R T (1998) The effects of spaceflight on mRNA levels for cytokines in proximal tibia of ovariectomized rats. Aviat Space Environ Med 69:626-9
Turner, R T; Evans, G L; Cavolina, J M et al. (1998) Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats. Endocrinology 139:4086-91
Westerlind, K C; Fluckey, J D; Gordon, S E et al. (1998) Effect of resistance exercise training on cortical and cancellous bone in mature male rats. J Appl Physiol 84:459-64
Sibonga, J D; Bell, N H; Turner, R T (1998) Evidence that ibuprofen antagonizes selective actions of estrogen and tamoxifen on rat bone. J Bone Miner Res 13:863-70
Westerlind, K C; Wronski, T J; Ritman, E L et al. (1997) Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain. Proc Natl Acad Sci U S A 94:4199-204
Jimenez, M A; Magee, D E; Bryant, H U et al. (1997) Clomiphene prevents cancellous bone loss from tibia of ovariectomized rats. Endocrinology 138:1794-800
Firling, C E; Evans, G L; Wakley, G K et al. (1996) Lack of an effect of sodium zeolite A on rat tibia histomorphometry. J Bone Miner Res 11:254-63
Turner, R T (1995) Effects of short-term spaceflight and recombinant human growth hormone (rhGH) on bone growth in young rats. Aviat Space Environ Med 66:763-9

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