O papel dos metabólitos da via 5-lipoxigenase na remodelação óssea induzida por força mecânica

Abstract

Bone remodeling, induced by mechanical force, results in bone resorption and bone deposition in specific sites and is regulated by the release of inflammatory mediators, among those, arachidonic acid (AA). AA, can be metabolized by 5-lipoxygenase (5-LO) pathway resulting in leukotriene B4 (LTB4) and cysteinyl leukotriene (CysLTs) formation. This metabolites of this pathway have long been studied in inflammatory response and, more recently, in bone remodeling. Thus, the aims of this study were i) develop a bone remodeling model during tooth movement induced by mechanical loading. ii) Investigate the role of 5-LO metabolites in bone remodeling and in osteoclast differentiation and recruitment. First, for ideal mechanical force definition for this model, C57BL/6 mice were submitted to orthodontic forces ranging from 0.1 N to 0.5 N. The ideal orthodontic force, 0.35 N, was used in the following groups: C57BL/6 or SV 129 (Wild Type-WT); 5-LO knockout (5-LO-/-) or treated with vehicle (VH), zileuton (ZN) (5-LO inhibitor) and montelukast (MT) (antagonist of the receptor of CysLTs). The amount of tooth movement and osteoclast numbers were evaluated histomorphometrically. Cytokine and bone remodeling expression was evaluated in compression and tension strains of the periodontium. The effect of 5-LO metabolites in osteoclast differentiation and also in TNF- release were evaluated in vitro in RAW 264.7 cells stimulated with LTB4 and LTD4. The 0.35 N force promoted tooth movement and osteoclast recruitment without root resorption. Tooth movement and osteoclast numbers were diminished in the absence or inhibition of 5-LO and treatment with CysLTs (MT) comparing to the respective WT and VH groups. It was observed the differential expression of cytokine and bone remodeling markers in tension and compression sites. Cathepsin K and TNF- were more expressed in compression site and OCN and RUNX2 in tension site. Moreover, TNF-, IL-10, RUNX2 and RANK expression diminished in 5-LO-/- and MT groups comparing to WT and VH, respectively. Also, TNF-, IL-10 and RUNX2, were diminished in ZN group compared to its VH. In vitro experiment demonstrated that LTB4 promoted more osteoclast differentiation than control and LTB4 and LTD4 increased TNF- release. Our results demonstrated the 5-LO metabolites, LTB4 and CysLTs, contribution to osteoclast recruitment and differentiation and consequently bone remodeling.