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 osteoclast-like 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. Identification of the local soluble mediators which stimulate osteoclastic bone resorption should enhance our understanding of the hormonal mechanisms responsible for increased bone resorption in normal bone remodeling and in all pathologic states in which bone resorption is increased.
