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SECOND INTERNATIONAL SYMPOSIUM
ON THE ROLE OF SOY
IN PREVENTING AND TREATING CHRONIC DISEASESeptember 15-18, 1996
Brussells, Belgium
SCIENTIFIC PROGRAM
(Oral Abstracts)Soy and Bone Health
Action of Genistein and Other Tyrosine Kinase Inhibitors in Preventing Osteoporosis.
Harry C. Blair, Associate Professor of Pathology, University of Alabama School of Medicine, Birmingham, AL 35294-0007, USA.Osteoporosis results when the rate of osteoclastic bone degradation exceeds bone formation. Osteoclasts are unusually dependent on tyrosine kinase activity; thus, tyrosine kinase inhibitors are candidates to prevent osteoporosis. However, most tyrosine kinase inhibitors are toxic. We compared efficacy and toxicity of genistein, a naturally occurring isoflavone tyrosine kinase inhibitor, with other
inhibitors, tyrphostins and herbimycin, using isolated avian osteoclasts. Inactive analogs were used to determine nonspecific effects. None of the tyrosine kinase inhibitors affected osteoclastic bone attachment. Genistein and herbimycin inhibited bone resorption with half maximal effects at 3 M and 0.1 M respectively; tyrphostins and daidzein were inactive at concentrations below 30 M, where nonspecific toxic effects were noted. Genistein and herbimycin thus inhibit osteoclasts by a mechanism independent ofcellular attachment; the tyrphostins were inactive at meaningful doses. Further, we found that neither genistein nor herbimycin bound significantly to bone, unlike other osteoclast metabolic inhibitors. Osteoclastic protein synthesis was significantly inhibited only at concentrations three fold greater than those inhibiting bone degradation, while herbimycin reduced protein synthesis at 10 nM, suggesting much less toxicity for the isoflavone. To test whether genistein reduces osteoclastic activity without unacceptable toxicity in vivo, bone mass was measured in ovariectomized rats given 30 mol/day genistein, relative to untreated controls during one month. Weights of treated and control animals were indistinguishable, indicating no toxicity, but femoral weight in the treated group was 12% greater than controls (p<0.05). Recently, we have shown rapid (<5 min) direct effects of tyrosine kinase inhibitors on the key metabolic activity of osteoclasts, acid secretion, at concentrations approximately three fold greater than those affecting whole cell activity over 3 d. The soy isoflavone genistein and herbimycin inhibited acid transport in isolated osteoclast membrane vesicles; half maximal effects were at 10 and 2 M. We conclude that genistein suppresses osteoclastic function in vitro and in vivo at concentrations consistent with a tyrosine kinase mechanism, and has low toxicity.
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