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Cytochrome P-450 inhibition blocks bone resorption in vitro and in vivo
1Department of Otolaryngology, Chungbuk National University College of Medicine, Cheongju, South Korea.
Abstract:
Although the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism have been shown to lead to osteoclastic resorption, the cytochrome P450 pathway has not been implicated. We investigated the effects of the cytochrome P450 pathway in IL-1beta-induced calcium release from cultured mouse calvaria in vitro in the presence of clotrimazole, a cytochrome P450 inhibitor, or L-N(G)-arginine methyl ester, a nitric oxide synthase inhibitor. Clotrimazole inhibited calcium release in a dose-dependent manner; however, L-N(G)-arginine methyl ester did not inhibit resorption. These results suggest that cytochrome P450 may be another possible mediator of IL-1beta-induced bone resorption in vitro. In the in vivo portion of the study, clotrimazole was administered in the gerbil model of adaptive bone modeling. Clotrimazole inhibited osteoclast surface; however, it did not reduce the osteoclast number, mean erosion surface per osteoclast, mineralization surface, or mineral-apposition rate. These results suggest that clotrimazole may inhibit the activation of osteoclasts and that cytochrome P450-dependent enzymes may be related to osteoclast activation in vivo.
Insights
The cytochrome P450 pathway, specifically inhibited by clotrimazole, was found to mediate interleukin-1beta-induced bone resorption in vitro. In vivo, clotrimazole inhibited osteoclast surface, suggesting a role in osteoclast activation.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- The cyclooxygenase and lipoxygenase pathways are known mediators of osteoclastic bone resorption.
- The role of the cytochrome P450 pathway in bone resorption has not been previously established.
Purpose of the Study:
- To investigate the involvement of the cytochrome P450 pathway in interleukin-1beta (IL-1beta)-induced bone resorption.
- To examine the effects of clotrimazole, a cytochrome P450 inhibitor, on IL-1beta-induced calcium release in vitro and on bone modeling in vivo.
Main Methods:
- In vitro: Cultured mouse calvaria were treated with IL-1beta in the presence of varying concentrations of clotrimazole or L-N(G)-arginine methyl ester (a nitric oxide synthase inhibitor). Calcium release was measured.
- In vivo: Clotrimazole was administered to gerbils in a model of adaptive bone modeling. Osteoclast surface, number, erosion surface, mineralization surface, and mineral-apposition rate were assessed.
Main Results:
- In vitro, clotrimazole significantly inhibited IL-1beta-induced calcium release in a dose-dependent manner, while L-N(G)-arginine methyl ester had no effect.
- In vivo, clotrimazole reduced osteoclast surface but did not alter osteoclast number, erosion surface, mineralization surface, or mineral-apposition rate.
Conclusions:
- The cytochrome P450 pathway is implicated as a mediator of IL-1beta-induced bone resorption in vitro.
- Clotrimazole's effects in vivo suggest it may inhibit osteoclast activation, indicating a potential role for cytochrome P450-dependent enzymes in osteoclast activation.