In an attempt to identify local mediators which activate mature osteoclasts directly, we found that a stromal cell line derived from a human giant cell tumor of bone was the source of an activity which was a more powerful stimulator of avian and rat osteoclasts (as well as the human giant cells) than any other source or mediator we have studied. We have undertaken identification of this activity, and found it is due to several products of arachidonic acid metabolism in the 5-lipoxygenase (5-LO) pathway. In this proposal, 1) we plan to identify and characterize all of the compounds of the 5-LO pathway which stimulate osteoclast activity, 2) to determine whether this is a common mechanism by which bone resorption is enhanced by cells in the osteoblast lineage, 3) to study mechanisms by which expression of enzymes in the 5-LO pathway are regulated by osteotropic hormones and cytokines and 4) to identify and characterize the property of C433 conditioned media which prevents degradation of unstable 5-LO metabolites. An understanding of the mechanisms by which giant cells are stimulated to resorb bone in human giant cell tumors of bone may increase not only our understanding of the mechanisms of bone loss in this condition, but also may improve our understanding of the mechanisms by which osteoclasts are activated by accessory cells during normal bone remodeling and in other pathological states.
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