The relevance of leukotrienes for bone resorption induced by mechanical loading

Abstract

5-Lipoxygenase (5-LO) metabolites are important pro-inflammatory lipid mediators. However, much still remains to be understood about the role of such mediators in bone remodeling. This study aimed to investigate the effect of 5-LO metabolites, LTB4 and CysLTs, in a model of mechanical loading-induced bone remodeling. Strain-induced tooth movement and consequently alveolar bone resorption/apposition was achieved by using a coil spring placed on molar and attached to incisors of C57BL6 (wild-type-WT), 5-LO deficient mice (5-LO−/−) and mice treated with 5-LO inhibitor (zileuton—ZN) or with antagonist of CysLTs receptor (montelukast—MT). The amount of bone resorption and the number of osteoclasts were determined morphometrically. The expression of inflammatory and bone remodeling markers in periodontium was analyzed by qPCR. Osteoclast differentiation and TNF-α production were evaluated in vitro using RAW 264.7 cells treated with LTB4 or LTD4. Bone resorption, TRAP+ cells and expression of Tnfa, Il10 and Runx2 were significantly diminished in 5-LO−/−, ZN- and MT-treated mice. The expression of Rank was also reduced in 5-LO−/− and MT-treated mice. Accordingly, LTB4 and LTD4 in association with RANKL promoted osteoclast differentiation and increased TNF-α release in vitro. These data demonstrate that the absence of 5-LO metabolites, LTB4 and CysLTs reduces osteoclast recruitment and differentiation, consequently diminishing bone resorption induced by mechanical loading. Thus, 5-LO might be a potential target for controlling bone resorption in physiological and pathological conditions.