A Critical Role for Adrenomedullin-Calcitonin Receptor-Like Receptor in Regulating Rheumatoid Fibroblast-Like Synoviocyte Apoptosis

Abstract

Rheumatoid arthritis (RA) is characterized by fibroblast-like synoviocyte (FLS) hyperplasia, which is partly ascribable to decreased apoptosis. In this study, we show that adrenomedullin (ADM), an antiapoptotic peptide, is constitutively secreted in larger amounts by FLS from joints with RA (RA-FLS) than with osteoarthritis (OA-FLS). ADM secretion was regulated by TNF-α. Peptidylglycine α-amidating monooxygenase, the ADM-processing enzyme, was expressed at the mRNA level by both RA-FLS and OA-FLS. Constituents of the ADM heterodimeric receptor calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP)-2 were up-regulated at the mRNA and protein levels in cultured RA-FLS compared with OA-FLS. ADM induced rapid intracellular cAMP production in FLS and reduced caspase-3 activity, DNA fragmentation, and chromatin condensation in RA-FLS exposed to apoptotic conditions, indicating that CRLR/RAMP-2 was fully functional. ADM-induced cAMP production was less marked in OA-FLS than in RA-FLS, suggesting differences in receptor regulation and expression. ADM dose-dependently inhibited RA-FLS apoptosis, and this effect was reversed by the 22–52 ADM antagonist peptide. ADM inhibited RA-FLS apoptosis triggered by extrinsic and intrinsic pathways. Our data suggest that ADM may prevent or reduce RA-FLS apoptosis, via up-regulation of its functional receptor CRLR/RAMP-2. Regulation of ADM secretion and/or CRLR/RAMP-2 activation may constitute new treatment strategies for RA.

Adrenomedullin RegulatesIL-1βGene Expression in F4/80+ Macrophages during Synovial Inflammation

“…In addition, RAMP3 expression in synovial macrophages was markedly higher compared to that detected in fibroblasts and was also stimulated by exogenously added IL-1 β . Uzan et al also reported that RAMP3 protein was not detectable in synovial fibroblasts from RA patients [28]. The present findings suggest that AM acts on synovial macrophages through RAMP3 during synovial inflammation.…”

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…They demonstrate pseudotumorlike overgrowth and resist apoptosis (42)(43)(44). The present study demonstrated the pivotal roles the CX 3 CR1 pathway plays in senescent CD4ϩ,CD28Ϫ T cell and FLS interaction and in the T cell-induced overgrowth of rheumatoid FLS.…”

Genome-wide transcriptional response of primary alveolar macrophages following infection with porcine reproductive and respiratory syndrome virus

“…IL-10 has been demonstrated to protect cells against apoptosis (Sieg et al , 1996; Zhou et al , 2001). ADM has been shown (Kubo et al , 1998) to be overproduced by macrophages after inflammation and to modulate cytokine production (specifically TNF- α ); several different independent studies support the fact that ADM is an anti-apoptotic peptide on different cell types (Bi et al , 2007; Uzan et al , 2006; Yin et al , 2004). TNF- α IP3 is a cytoplasmic zinc finger protein that inhibits NF- κβ activity and TNF-mediated programmed cell death (Li et al , 2006; Qin et al , 2006).…”