During life, bone is being constantly resorbed and reformed in a process known as bone remodeling. Any disturbance in this process can result in bone diseases such as osteopetrosis and osteoporosis. The osteoclast is the bone cell responsible for resorption of the bone matrix. The mechanism by which these cells are stimulated to resorb bone is not known. Metabolites of the 5-lipoxygenase pathway have been shown to stimulate osteoclasts to resorb bone in a number of in vitro and in vivo bone resorbing systems, and could be responsible for bone loss due to inflammatory bone disease. During osteoclast ontogeny, the osteoclast precursor proliferates, differentiates and fuses to form a multinucleated cell, the mature osteoclast, which is capable of resorbing bone. The present studies were initiated to determine where in the osteoclast differentiation pathway 5-lipoxygenase metabolites are acting. The peptidoleukotrienes appear to have direct effects on mature osteoclasts, however, leukotriene B4, another metabolite of this pathway, appears to be having more dramatic effect on osteoclast precursors. LTB4 was found to be a fusogen which causes the osteoclast precursors to fuse to form multinucleated cells. Experiments were initiated to determine if inhibitors of the 5-lipoxygenase pathway would block the formation of osteoclasts. An inhibitor called ZM230,487 was found to be a potent inhibitor of osteoclast formation. This specific inhibitor of the 5-lipoxygenase enzyme binds to the enzyme in a chiral fashion to the active site. However, the non-specific 5-LO inhibitor nordihydroguaiaretic acid had no effect on osteoclast formation. These preliminary results suggest that the mechanism of action of ZM230,487 on decreasing osteoclast formation may not be via the 5-lipoxygenase pathway.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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