5-Lipoxygenase metabolites inhibit bone formation in vitro.
The leukotrienes and peptido-leukotrienes are 5-lipoxygenase (5-LO) metabolites of arachidonic acid that appear to have unique effects on bone, distinct from those of the prostaglandins. Application of exogenous leukotrienes in vitro and in vivo results in increased osteoclast formation and bone resorption. While 5-LO metabolites of arachidonic acid clearly stimulate osteoclastic bone resorption, little is known concerning their effects on osteoblastic bone formation. We examined the effects of the 5-LO metabolites 5-HETE, the leukotriene LTB4 and, as representative of the peptido-leukotrienes, LTD4 on the formation of mineralized nodules of fetal rat calvarial cells in the presence of dexamethasone and recombinant human bone morphogenetic protein-2 (rhBMP-2). We also examined the effects of these 5-LO metabolites on alkaline phosphatase activity and cell proliferation in these cultures and the effects of 5-HETE and LTB4 on cultured explants of neonatal murine calvariae. We found that the bone-forming capacity of osteoblasts was impaired when cells were cultured in the presence of 5-LO metabolites. These data indicate that metabolites of the 5-LO pathway are negative regulators of bone formation. The continued presence of these metabolites in the bone environment might account, in part, for the bone loss associated with chronic inflammatory conditions.
Traianedes
K
K
The University of Texas Health Science Center at San Antonio, 78284-7877, USA.
Dallas
M R
MR
Garrett
I R
IR
Mundy
G R
GR
Bonewald
L F
LF
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012886:Skull / Q000166:cytology / Q000196:embryology*; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D005938:Glucocorticoids; D006893:Hydroxyeicosatetraenoic Acids; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D017998:Leukotriene D4; D003907:Dexamethasone; D000469:Alkaline Phosphatase