Adrenomedullin increases fibroblast-like synoviocyte adhesion to extracellular matrix proteins by upregulating integrin activation

作者：Kioon Marie Dominique Ah; Asensio Carine; Ea Hang Korng; Uzan Benjamin; Cohen Solal Martine; Liote Frederic^*

来源：Arthritis Research and Therapy, 2010, 12(5): R190.

DOI：10.1186/ar3160

Introduction: Rheumatoid arthritis (RA) is characterized by bone and cartilage invasion by fibroblast-like synoviocytes (FLSs). Adrenomedullin, a peptide with anabolic and antiapoptotic properties, is secreted by rheumatoid FLSs. Adrenomedullin also increases the expression of adhesion molecules in endothelial cells and keratinocytes. Here, we investigated whether adrenomedullin mediated FLS adhesion to extracellular matrix (ECM) proteins.
Methods: FLSs were isolated from synovial tissues from RA and osteoarthritis (OA) patients. Plates were coated overnight with the ECM proteins vitronectin, fibronectin, and type I collagen (Coll. I). Adrenomedullin was used as a soluble FLS ligand before plating. We tested interactions with the adrenomedullin receptor antagonist (22-52) adrenomedullin and with the protein kinase A (PKA) inhibitor H-89, and inhibition of co-receptor RAMP-2 by siRNA. Cell adhesion was measured by using color densitometry. Activation of alpha(2) and beta(1) integrins was evaluated by fluorescent microscopy; integrin inhibition, by RGD peptides; and the talin-integrin interaction, by immunoprecipitation (IP).
Results: Adrenomedullin specifically increased RA-FLS adhesion to vitronectin, fibronectin, and Coll. I; no such effect was found for OA-FLS adhesion. Basal or adrenomedullin-stimulated RA-FLS adhesion was inhibited by (22-52) adrenomedullin, H-89, and RAMP-2 siRNA. Adrenomedullin-stimulated adhesion was inhibited by RGD peptides, and associated with alpha(2) and beta(1) integrin activation. This activation was shown with IP to be related to an integrintalin interaction and was significantly decreased by (22-52) adrenomedullin.
Conclusions: Adrenomedullin-stimulated RA-FLS adhesion was specific for ECM proteins and mediated by alpha(2) and beta(1) integrins. This effect of adrenomedullin was dependent on adrenomedullin receptors. These results support a new role for adrenomedullin in rheumatoid synovial fibroblast pathobiology.

• 出版日期2010