| Texto completo | |
| Autor(es): |
Denadai-Souza, Alexandre
;
Ribeiro, Camilla Moreira
;
Rolland, Corinne
;
Thouard, Anne
;
Deraison, Celine
;
Scavone, Cristoforo
;
Gonzalez-Dunia, Daniel
;
Vergnolle, Nathalie
;
Werneck Avellar, Maria Christina
Número total de Autores: 9
|
| Tipo de documento: | Artigo Científico |
| Fonte: | ARTHRITIS RESEARCH & THERAPY; v. 19, JUN 6 2017. |
| Citações Web of Science: | 6 |
| Resumo | |
Background: Increasing evidences indicate that an unbalance between tryptases and their endogenous inhibitors, leading to an increased proteolytic activity, is implicated in the pathophysiology of rheumatoid arthritis. The aim of the present study was to evaluate the impact of tryptase inhibition on experimental arthritis. Methods: Analysis of gene expression and regulation in the mouse knee joint was performed by RT-qPCR and in situ hybridization. Arthritis was induced in male C57BL/6 mice with mBSA/IL-1 beta. Tryptase was inhibited by two approaches: a lentivirus-mediated heterologous expression of the human endogenous tryptase inhibitor, sperm-associated antigen 11B isoform C (hSPAG11B/C), or a chronic treatment with the synthetic tryptase inhibitor APC366. Several inflammatory parameters were evaluated, such as oedema formation, histopathology, production of IL-1 beta, -6, -17A and CXCL1/KC, myeloperoxidase and tryptase-like activities. Results: Spag11c was constitutively expressed in chondrocytes and cells from the synovial membrane in mice, but its expression did not change 7 days after the induction of arthritis, while tryptase expression and activity were upregulated. The intra-articular transduction of animals with the lentivirus phSPAG11B/C or the treatment with APC366 inhibited the increase of tryptase-like activity, the late phase of oedema formation, the production of IL-6 and CXCL1/KC. In contrast, neutrophil infiltration, degeneration of hyaline cartilage and erosion of subchondral bone were not affected. Conclusions: Tryptase inhibition was effective in inhibiting some inflammatory parameters associated to mBSA/IL-1 beta-induced arthritis, notably late phase oedema formation and IL-6 production, but not neutrophil infiltration and joint degeneration. These results suggest that the therapeutic application of tryptase inhibitors to rheumatoid arthritis would be restrained to palliative care, but not as disease-modifying drugs. Finally, this study highlighted lentivirus-based gene delivery as an instrumental tool to study the relevance of target genes in synovial joint physiology and disease. (AU) | |
| Processo FAPESP: | 12/07784-4 - Avaliação do efeito da expressão heteróloga de variantes de splice alternativo do gene hSPAG11B no desenvolvimento de artrite inflamatória em camundongos C57BL/6 selvagens ou nocaute para F2rl1 (PAR2) |
| Beneficiário: | Alexandre Denadai Souza |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado |
| Processo FAPESP: | 10/52711-0 - Aspectos funcionais da proteina spag11, papel fisiologico e mecanismo de acao. |
| Beneficiário: | Maria Christina Werneck de Avellar |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 09/12375-3 - Papel da proteína SPAG11 na modulação da artrite experimental |
| Beneficiário: | Alexandre Denadai Souza |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |