The Role of LTB4 in Osteodastic Bone Resorption Leukotrienes are inflammatory mediators generated from arachidonic acid. They have been shown to be elevated in conditions such as asthma, arthritis and periodontal disease. Recently, it has been shown that these compounds may also play a destructive role in the bone microenvironment. The formation of the leukotrienes is catalyzed by the enzyme S-lipoxygenase (SLO). SLO co-localizes to the nuclear membrane with SLO activating protein (FLAP) and acts to convert arachidonic acid to the intennediate S-hydroperoxyeicosatetraenoic acid (5-HPETE). This compound can be acted upon again by SLO to generate leukotriene A4 (LTA4) which is later converted to leukotriene B4 (LTB4) or to the peptidoleukotrienes (LTC4, LTD4, and LTE4). Both LTB4 and the peptidoleukotrienes have been shown to stimulate bone resorption. One of the peptidoleukotrienes, LTD4, has been shown to have potential for direct effects on the osteoclast, the bone resorbing cell. Hypotheses: (1) LTB4 has its effect on bone resorption by direct action on the osteoclast, (2) 5LO metabolites are mediators in the effect of 1,25 dihydroxyvitamin D3 [1,25(0H)2D3] on osteoclast formation, (3) osteoclasts are a source of SLO metabolites in the bone microenvironment.
Specific Aims : (1) Demonstrate the direct effects of LTB4 on osteoclasts in vitro. (2) Determine the role of SLO metabolites in the action of a known stimulator of osteoclast formation, 1,25(0H)2D3, in vitro. (3) Determine whether osteoclasts or their precursors are a source of the leukotrienes in the bone microenvironment. Significance: An anti-leukotriene medication has already been developed and marketed and is in use for the treatment of asthma. Elucidation of the role and mechanism of leukotrienes in inflammatory bone loss may provide a new therapeutic use for these agents.
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