A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss.
Although leukotriene B(4) (LTB(4)) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB(4) receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB(4) receptor BLT2, and produced LTB(4). LTB(4) changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB(4) increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.
Hikiji
Hisako
H
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ishii
Satoshi
S
Yokomizo
Takehiko
T
Takato
Tsuyoshi
T
Shimizu
Takao
T
D000818:Animals; D001862:Bone Resorption / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D048430:Cell Shape / Q000187:drug effects; D007975:Leukotriene B4 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction
C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D002118:Calcium