O papel da fosfatidilinositol-3-cinase (pi3k) na remodelação dos ossos maxilares

Abstract

Introduction: Bone is a dynamic tissue that undergoes constant physiological remodeling. The bone remodeling process is coordinated by several local and systemic factors, and phosphatidylinositol-3-kinase (PI3K) has been associated with bone cell function. However, as far as we are concerned, there are no studies that investigated PI3Kγ function on induced bone remodeling in the maxilla. Aim: To investigate the role of PI3Kγ in the mechanically induced bone remodeling. Methods: In this study, male wild C57BL6 / J (WT) mice, male mice deficient for PI3Kγ (PI3Kγ-/-), and male mice with loss of the kinase activity of the enzyme PI3Kγ (PI3KγKD/KD). The induction of bone remodeling was performed by orthodontic tooth movement (OTM). A spring was installed and positioned between the first right upper molar and the central incisors, and opening loops were positioned on the molars whit aim of rapid maxillary expansion (RME). After euthanasia, the jaws were analyzed by computerized microtomography (microCT), histomorphometric and gene expression was performed for osteoblast markers (OBL), osteoclasts (OCL), and inflammatory molecules by polymerase chain reaction (RT-PCR). The PI3K signaling pathway was evaluated by Western blot. The femurs were analyzed by microCT and bone marrow cells were differentiated into OBL and OCL. Results: The maxillary and palate bones of PI3Kγ-/- and PI3KγKD/KD animals showed an increase in bone microarchitecture compared with WT animals. After inducing bone remodeling in PI3Kγ-/- animals, there was a reduction in OTM and RME, with a greater number of OBL and a lower OCL count in the maxillary bones after OTM. Corroborating these findings, there was an increase in bone formation markers, Runx2 and Alp, a reduction in the pro- inflammatory gene Il-6, as well as a lack of responsiveness to bone resorption inducing genes such as Rankl. The maxillary bones of PI3Kγ-/- animals showed less protein activity in the p- Akt signaling pathway. The tooth root and femur of the PI3Kγ-/- animals showed a phenotype similar to that of the maxillary bone. Cell culture revealed a greater area of osteoblast mineralization in the cells of PI3Kγ-/- animals and less differentiation of osteoclasts. The absence of PI3Kγ provided an increase in bone and root microarchitecture, proving to be an important molecule in the differentiation and signaling cascade of bone cells. The data obtained are fundamental in order to conduct future therapeutic strategies in bone modulation.