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Role of NETs as osteoclastogenesis modulators in Rheumatoid Arthritis

Grant number: 19/19190-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2020
Effective date (End): December 31, 2023
Field of knowledge:Biological Sciences - Pharmacology
Principal researcher:Fernando de Queiroz Cunha
Grantee:Ayda Henriques Schneider
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Rheumatoid Arthritis (RA) is an autoimmune disease that causes cartilage and bone damage relationated with incapacitation. Studies have shown that osteoclasts inhibition reduces bone loss in RA. Denosumab, a monoclonal antibody anti-receptor activator of nuclear factor kappa-’ ligand (RANKL), is used as RA treatment, since the binding of RANKL to receptor activator of nuclear factor kappa-’ (RANK) participates in the osteoclasts differentiation and maturation. Thus, this pathway study can be used for the RA and other rheumatic diseases therapeutic treatment. It is known that Neutrophil Extracellular Traps (NETs) are important in RA, however, its relation with osteoclasts has not been elucidated. Preliminary data from this project suggest that NETs participate in RA osteoclastogenesis. Therefore, the objective of this work is evaluate if NETs contribute to the joints injury and identify the mechanisms through which NETs can induce osteoclastogenesis during RA. In order to do this, we will use RA murine models, such as Collagen-Induced Arthritis (CIA) and adjuvant-induced arthritis (AIA), in which the NETs presence will be controlled by three ways: pharmacologically, using DNaseI that promotes their degradation; with CL-amidine, a PAD4 inhibitor, an enzyme involved in the NETs formation; and with the PADI4 gene deletion, the gene that promotes the PAD4 enzyme transcription. Histological sections and specific markers will be used for joints injury and osteoclastogenesis determination. The osteoclastogenesis will also be evaluated in vitro from osteoclasts culture stimulated with purified NETs. Finally, we will study the association between NETs increase and osteoclastogenesis related factors in RA patients. (AU)

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