Synovial fibroblasts are known to have a role in cartilage destruction in the setting of inflammatory arthritis, mainly via production of IL-6. Cadherin 11 (CDH11), which is selectively expressed on fibroblasts, has been implicated as an important mediator of inflammation: anti-CDH11 monoclonal antibodies reduced inflammation in a mouse model of arthritis, and mice deficient in CDH11 exhibited reduced damage to articular cartilage. Chang and colleagues have now elucidated the mechanism by which CDH11 facilitates fibroblast inflammation.

Stimulation of cultured synovial fibroblasts from patients with rheumatoid arthritis (RA), using a CDH11–Fc fusion protein designed to mimic cell–cell CDH11 engagement, induced IL-6 production in a dose-dependent manner. A cytokine antibody array showed that CDH11 also significantly increased the secretion of CC-chemokine ligand 2, CXC-chemokine ligand 1, IL-8 and macrophage migration inhibitory factor. These findings indicate that CDH11 acts as a signaling receptor that can induce secretion of proinflammatory factors by synovial fibroblasts.

The authors then set out to characterize the signaling pathways activated by CDH11 engagement. Immunoblotting analysis showed that the mitogen-activated protein kinases (MAPKs) JNK and ERK and the transcription factor nuclear factor κB (NFκB)—which are known to have a role in IL-6 production when activated—were all phosphorylated following CDH11–Fc stimulation of synovial fibroblasts.

To emulate the role of CDH11 in an inflammatory microenvironment, such as that in the RA synovium, fibroblasts were stimulated with CDH11–Fc in the presence of tumor necrosis factor (TNF) and IL-1β. These two cytokines were applied to cultured synovial fibroblasts at levels below those necessary to strongly induce IL-6. When CDH11–Fc was added, IL-6 secretion was induced at significantly higher levels than those observed with stimulation by TNF, IL-1β or CDH11–Fc alone. These data suggest a synergistic effect of CDH11 engagement with other inflammatory cytokines in terms of IL-6 production, which might contribute to initiation or propagation of inflammation in arthritis.

Finally, the effect of CDH11 on IL-6 production was tested in vivo, using the K/BxN serum transfer model of inflammatory arthritis in wild-type and CDH11-deficient B6 mice. TNF and IL-6 expression, ankle thickness and clinical inflammation scores were all significantly decreased in CDH11-deficient mice compared with wild-type animals, indicating that CDH11 influences cytokine production in the synovium in vivo.

The authors conclude that CDH11 seems to have an important role in synovial fibroblast activation and inflammation via MAPK and NFκB signaling.