Role of NETs as osteoclastogenesis modulators in Rheumatoid Arthritis

• Grant number: 19/19190-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2020
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Ayda Henriques Schneider
• Host 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
• Associated scholarship(s): 22/13018-4 - Role of neutrophil extracellular traps on the production of resolution mediators in bone loss, BE.EP.DR

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SCHNEIDER, AYDA HENRIQUES; TAIRA, THAISE MAYUMI; PUBLIO, GABRIEL AZEVEDO; PRADO, DOUGLAS DA SILVA; YABUTA, PAULA BARBIM DONATE; DOS SANTOS, JESSICA CRISTINA; MACHADO, CAIO CAVALCANTE; DE SOUZA, FLAVIO FALCAO LIMA; VENTURINI, LUCAS GABRIEL RODRIGUES; DE OLIVEIRA, RENE DONIZETI RIBEIRO; et al. Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis. British Journal of Pharmacology, v. N/A, p. 18-pg., 2023-09-28. (13/08216-2, 19/19190-0)

CORSI-ZUELLI, FABIANA; HENRIQUES SCHNEIDER, AYDA; SANTOS-SILVA, THAMYRIS; MARCELINO LOUREIRO, CAMILA; SHUHAMA, ROSANA; ROSSI MENEZES, PAULO; SILVEIRA GUIMARAES, FRANCISCO; VILLELA GOMES, FELIPE; QUEIROZ CUNHA, FERNANDO; LOUZADA, PAULO; et al. Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model. TRANSLATIONAL PSYCHIATRY, v. 12, n. 1, p. 11-pg., 2022-12-26. (13/08216-2, 13/11167-3, 18/17597-3, 12/05178-0, 19/19190-0, 19/13229-2, 21/07448-3, 20/15752-1, 17/24304-0)