Journal
BONE
Volume 28, Issue 2, Pages 167-173Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S8756-3282(00)00425-7
Keywords
alcohol; osteoblast; signal transduction; kinase; interleukin-6; cytokine
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Funding
- NIA NIH HHS [R01 AG15904] Funding Source: Medline
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Alcoholics frequently suffer from moderate to severe bone loss that results in bone fractures. Both decreased bone production and increased bone resorption have been postulated to contribute to ethanol (ETOH)-mediated bone loss. Bone resorption is induced by several proinflammatory cytokines such as interleukin-1 and -6, The expression of these cytokines is induced by the transcription factor NF kappaB, which, in turn, is activated by several kinases. It follows that protein kinase and NF kappaB activation may contribute to ETOH-induced bone loss, Accordingly, we sought to determine if ETOH activates protein tyrosine kinases (PTK) and NF kappaB DNA binding in a human osteoblast-like cell line (HOBIT), Ethanol at 50 and 100 mmol/L (reflective of blood ethanol levels reached in chronic alcoholics) for 24 h did not alter HOBIT cell viability. In contrast, 200 mmol/L ethanol decreased cell viability by 40%. Treatment of HOBIT cells with 100 mmol/L ETOH induced nuclear NF kappaB:DNA complex formation and NF kappaB activity. Incubation of HOBIT cells with ETOH at 50 and 100 mmol/L for 30 min induced a 2.5- and 4.2-fold increase in PTK activity, respectively, Preincubation of HOBIT cells with damnacanthal (DAM), which inhibits p56(lck), blocked ETOH-mediated PTK activity; whereas, preincubation with herbimycin A, which inhibits pp60(src), did not. DAM inhibited both ethanol-induced NF kappaB activation in HOBIT cells and interleukin-6 expression in primary human osteoblasts. Finally, preincubation with the protein kinase C inhibitor, bisindolylmaleimide I HCl (BIS), diminished ETOH-mediated PTK activity; whereas, preincubation with the protein kinase A inhibitor, H89, did not. These data demonstrate that ETOH induces NF kappaB nuclear translocation through p56(lck) in HOBIT cells. BIS' inhibition of PTK activation suggests that ETOH activates PTK through a protein kinase C-dependent pathway. These data suggest that ETOH may contribute to bone loss through activation of signal transduction that results in production of an osteoclastogenic cytokine interleukin-6) in osteoblasts. (Bone 28:167-173; 2001) (C) 2001 by Elsevier Science Inc, All rights reserved.
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