The role of succinate (SUCNR1/GPR91) in the periodontitis formation and bone loss in an experimental model of apical lesion

• Grant number: 23/18097-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2024
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Dentistry - Endodontics
• Principal Investigator: Sandra Yasuyo Fukada Alves
• Grantee: Julio Cesar Ramos Cadilho
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 19/08568-2 - Investigation of the extracellular vesicles (VEs) role in the initiation, propagation, regeneration, and modeling of biological mineralization, AP.TEM

Abstract

The apical periodontitis consists of an inflammatory/infectious disease originating from the invasion of microorganisms into dental pulp, spreading to the dental apex and extensively destroying periapical tissues. An abnormal elevation of succinate has been observed in the subgingival plaque of individuals with severe periodontal disease. Succinate activates the succinate receptor-1 (SUCNR1) and stimulates inflammation. This metabolite may play a crucial role in the pathogenesis of periodontal disease, particularly as succinate production by bacteria increases the expression of virulence associated genes, potentially contributing to disease severity. Additionally, the activation of this receptor stimulates osteoclast differentiation. Thus, the aim of this study is to investigate the role of succinate in the development of inflammatory lesions and bone loss in a mouse model of induced apical injury, using SUCNR1-deficient mice and selectively in osteoclasts (CtskCre - SUCNR1flox). Furthermore, the study aims to uncover the mechanisms involved in the enhanced osteoclast differentiation induced by succinate. To this end, SUCNR1KO, CtskCre, and CtskCre - SUCNR1flox/flox animals will be submitted to the apical lesion model. The extent of the lesion will be assessed at lesion site through histology and microCT; osteoclast marker expression will be evaluated by qPCR and confirmed by TRAP enzymatic assay; and metalloproteinase activity will be examined through zymography. Additionally, the impact of succinate on osteoclast differentiation and function will be investigated in vitro using bone marrow cells stimulated with RANKL and varying concentrations of succinate.