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Peptides. 2017 Sep;95:57-61. doi: 10.1016/j.peptides.2017.07.008. Epub 2017 Jul 18.

Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.

Author information

1
Laboratório de Doenças Autoimunes, Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Ramiro Barcellos Sreet, 2350, Room 645, 90035-003, Porto Alegre, RS, Brazil.
2
Departamento de Medicina, Universidade Federal do Rio Grande do Sul,Jerônimo de Ornellas Avenue, 721, 90040-001, Porto Alegre, RS, Brazil; Laboratório de Doenças Autoimunes, Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Ramiro Barcellos Sreet, 2350, Room 645, 90035-003, Porto Alegre, RS, Brazil.
3
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Division of Rheumatology, Icahn School of Medicine at Mount Sinai, 10029 NY, United States.
5
Departamento de Medicina, Universidade Federal do Rio Grande do Sul,Jerônimo de Ornellas Avenue, 721, 90040-001, Porto Alegre, RS, Brazil; Laboratório de Doenças Autoimunes, Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Ramiro Barcellos Sreet, 2350, Room 645, 90035-003, Porto Alegre, RS, Brazil. Electronic address: rxavier10@gmail.com.

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.

KEYWORDS:

Fibroblasts-like synoviocyte; Gastrin-releasing peptide receptor; PI3K/AKT pathway; RC-3095; Rheumatoid arthritis

PMID:
28733141
DOI:
10.1016/j.peptides.2017.07.008
[Indexed for MEDLINE]
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