> salicylamide is an antagonist of the aryl hydrocarbon ...
Inhibition of dioxin effects on bone formation in vitro by a newly
described aryl hydrocarbon receptor antagonist, resveratrol.
Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants
found in cigarette smoke and other sources of air pollution. The
prototypical compound is TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin),
also known as dioxin. There is an increasing body of knowledge linking
cigarette smoking to osteo****osis and periodontal disease, but the
direct effects of smoke-associated aryl hydrocarbons on bone are not
well understood. Through the use of resveratrol (3,5,4'-
trihydroxystilbene), a plant antifungal compound that we have recently
demonstrated to be a pure AhR antagonist, we have investigated the
effects of TCDD on osteogenesis. It was postulated that TCDD would
inhibit osteogenesis in bone-forming cultures and that this inhibition
would be antagonized by resveratrol. We employed the chicken
periosteal osteogenesis (CPO) model, which has been shown to form bone
in vitro in a pattern morphologically and biochemically similar to
that seen in vivo, as well as a rat stromal cell bone nodule formation
model. In the CPO model, alkaline phosphatase (AP) activity was
reduced by up to 50% (P<0.01 vs control) in the presence of 10(-9) M
TCDD and these effects were reversed by 10(-6) M resveratrol (P<0.05
vs TCDD alone). TCDD-mediated inhibition of osteogenesis was
restricted primarily to the osteoblastic differentiation phase (days
0-2) as later addition did not appear to have any effects. Message
levels for im****tant bone-associated proteins (in the CPO model) such
as collagen type I, osteopontin, bone sialoprotein and AP were
inhibited by TCDD, an effect that was antagonized by resveratrol.
Similar findings were obtained using the rat stromal bone cell line.
TCDD (at concentrations as low as 10(-10)M) caused an approximately
33% reduction in AP activity, which was abrogated by 3. 5x10(-7) M
resveratrol. TCDD also induced a marked reduction in mineralization
( approximately 75%) which was completely antagonized by resveratrol.
These data suggest that AhR ligands inhibit osteogenesis probably
through inhibition of osteodifferentiation and that this effect can be
antagonized by resveratrol. Since high levels of AhR ligands are found
in cigarette smoke, and further since smoking is an im****tant risk
factor in both osteo****osis and periodontal disease, it may be
postulated that AhR ligands are the component of cigarette smoke
linking smoking to osteo****osis and periodontal disease. If so,
resveratrol could prove to be a promising preventive or therapeutic
agent for smoking-related bone loss. PMID: 11018766
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