MicroRNAs role in bone impairment induced by periodontal disease and the local renin-angiotensin system in spontaneous hypertensive rats

Abstract

Periodontal disease (PD) is an inflammatory disorder of the teeth surrounding and supporting tissues. Although the microbial etiological factor is determinant, PD progression depends on a dynamic pathogen-host interaction and may be aggravated by pre-existing systemic diseases such as hypertension, with a high probability of coexistence with PD, as they share several risk factors. In addition, studies discuss a possible causality between hypertension and PD, showing a two-way relationship when associated. In Spontaneously Hypertensive Rats (SHR), an important model of essential hypertension, PD show an exacerbated inflammatory response, increased periodontal destruction and alveolar bone resorption, and some mechanisms potentially involved in this response have been proposed. The renin-angiotensin system (RAS) regulates several cardiocirculatory parameters, but in addition to its classic role, local renin-angiotensin systems, already described in different tissues including periodontal tissues, have been associated with inflammation and bone metabolism. Type 1 angiotensin II receptor antagonists is one of the most clinically used antihypertensive drug, and among the examples, telmisartan (TELM) attracts attention for its high selectivity, lipophilicity, long half-life, and for being the only in this class with partial agonist activity on PPAR-³ (Peroxisome Proliferator-Activated Gamma Receptor). Previous results from our laboratory showed a significant protective role of telmisartan in the local bone consequences of PD in hypertensive animals, being able to modulate the expression of different bone metabolism markers. MicroRNAs (miRs) are small non-coding interfering RNAs, capable of regulating the expression and translation of different targets and have been drawing attention since their discovery as an important mechanism for epigenetic regulation of physiological and pathological responses. Several studies have focused their efforts on the discovery of potential miRs involved with inflammatory responses, bone loss disorders and systemic diseases. In the present study, we aim to evaluate the role of miRs in PD-induced local bone alterations in an animal model of hypertension and its relationship with local RAS. Normotensive (Wistar rats) and hypertensive animals (SHR) with experimentally-induced PD (bilateral ligature of the first lower first molars, maintained for 15 days), and treated with TELM, will be used to evaluate the differential expression of microRNAs (array) in the alveolar bone, with subsequent in vitro functional studies of the major hits (up-regulated or down-regulated miRs) in alveolar bone-derived osteoblasts and bone marrow derived-osteoclasts by miRs inhibitors or mimics transfection. We intend to better understand the role of miRs in PD-induced local bone consequences in normotensive and hypertensive animals, and their relationship with local RAS, as these are important mechanisms, not yet fully understood. (AU)