The amine-carboxyboranes and related derivatives have been shown to be
potent anti-inflammatory and anti-osteoporosis agents. Their action in
part appears to be mediated by the modulation of cytokines, e.g. TNFα
or IL-1. Previous studies have demonstrated that LPS induced
macrophages release of TNFα maximally at 60 to 90 min. and IL-1 from 5
to 8 hr. The amine-carboxyboranes reduced significantly the release of
these cytokines but also blocked TNFα high affinity binding to UMR-106
receptor at 90 min. at 10 μM, and IL-1 high affinity binding at 5 hr. at
12.5 μM. In addition, the agents suppressed IL-8 binding to CHO K1 high
affinity receptor at 24 hr. at 50 μM and IL-2 binding to HuT-8 receptors
at 25 μM at 90 min. and 5 hr. Correlation of metabolic events
associated with osteoporosis showed that at 90 min., when TNFα receptor
binding was reduced by the agents, calcium uptake into UMR-106 cells was
reduced at 10 μM as well as the acid and alkaline phosphatases, and the
prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and
macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced
IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D3
binding was reduced by the agents as was acid and alkaline phosphatase,
and 5′-lipoxygenase activities and white blood cell adhesion. At this
time calcium uptake and proline incorporation was increased
significantly by the agents. At later times e.g. 18-48 hr. calcium
uptake was still increased, and NAG activity was inhibited in the
presence of the agents. These effects may be related more to the
inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of
the observed metabolic effects of amine-carboxyboranes as antiosteoporosis
agents can be correlated with their inhibition of cytokine
high affinity binding to target cell receptors.