LEUKOTRIENE B-4 STIMULATES OSTEOCLASTIC BONE-RESORPTION BOTH IN-VITROAND IN-VIVO

Upon activation, the enzyme 5-lipoxygenase converts arachidonic acid i nto principally three products, the peptido-leukotrienes, 5-hydroperox yeicosatetraenoic acid (5-HETE) or the leukotriene B-4. We have shown that the peptido-leukotrienes (known as LTC(4), LTD(4) or LTE(4)) and 5-HETE induce osteoclastic bone resorption and that receptors for LTD( 4) are present on isolated avian osteoclast-like cells. Here, we show the effects of the third metabolic product of the 5-lipoxygenase (5-LO ) pathway of arachidonic acid metabolism, the leukotriene LTB(4), on o steoclastic bone resorption both in vivo and in vitro. Because LTB(4) production is increased in a number of inflammatory conditions, it may be an important contributor to the bone loss which occurs in these di sorders, LTB(4) increased osteoclastic bone resorption in vivo followi ng local administration over the calvariae of normal mice and in vitro in organ cultures of neonatal mouse calvariae, When LTB(4) was inject ed over the calvaria of mice, there was a significant increase in bone resorption, osteoclast numbers, and eroded surfaces, LTB(4) also incr eased the formation of resorption lacunae by isolated neonatal rat ost eoclasts. Greater potency was observed with LTB(4) compared with the p eptido-leukotriene LTD(4). This is in contrast to prostaglandins of th e E series, which are reported to inhibit isolated osteoclasts, Experi ments using marrow cultures suggest that LTB(4) stimulates bone resorp tion in part by enhancing the formation of osteoclasts.