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. 2024 Feb;181(3):429-446.
doi: 10.1111/bph.16227. Epub 2023 Sep 28.

Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis

Ayda Henriques Schneider  1   2 , Thaise Mayumi Taira  1   3 , Gabriel Azevedo Públio  1   2 , Douglas da Silva Prado  1   2 , Paula Barbim Donate Yabuta  1   2 , Jéssica Cristina Dos Santos  1   4 , Caio Cavalcante Machado  1   5 , Flávio Falcão Lima de Souza  1   5 , Lucas Gabriel Rodrigues Venturini  1   3 , Renê Donizeti Ribeiro de Oliveira  1   5 , Thiago Mattar Cunha  1   2 , José Carlos Alves-Filho  1   2 , Paulo Louzada-Júnior  1   5 , Tarcília Aparecida da Silva  1   6 , Sandra Yasuyo Fukada  1   3 , Fernando Queiróz Cunha  1   2
Affiliations
Free article

Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis

Ayda Henriques Schneider et al. Br J Pharmacol. 2024 Feb.
Free article

Abstract

Background and purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause bone erosion due to increased osteoclastogenesis. Neutrophils involvement in osteoclastogenesis remains uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis.

Experimental approach: The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro-CT in antigen-induced arthritis (AIA)-induced WT mice treated with DNase or in Padi4-deficient mice (Padi4flox/flox LysMCRE ). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from Tlr4-/- and Tlr9-/- mice were cultured with NETs.

Key results: Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL-induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions in vitro. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis.

Conclusions and implications: Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.

Keywords: NETs; bone damage; osteoclastogenesis; osteoclasts; rheumatoid arthritis.

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