Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation

Abstract

Objective. Cadherin 11 expressed on fibroblastlike synoviocytes (FLS) plays a key role in normal synovial architecture. The purpose of this study was to examine the expression of cadherin 11 in human synovitis.Methods. Cadherin 11 expression in synovial biopsy samples from patients with various types of arthritis and in lung biopsy samples from patients with interstitial pneumonitis (IP) was examined by immunostaining. The regulation of cadherin 11 expression in human FLS was assessed by quantitative reverse transcription-polymerase chain reaction analysis and Western blotting. Therapeutic modulation of synovial cadherin 11 was assessed before and after effective antiinflammatory therapy.Results. Abundant staining for cadherin 11 was seen in the intimal lining layer and the synovial sublining in inflamed tissues, with discrete staining in noninflammatory osteoarthritic (OA) tissues. The pattern and degree of immunostaining were similar in tissues from patients with rheumatoid arthritis (RA), nonpsoriatic spondylarthritis (SpA), psoriatic arthritis (PsA), and inflammatory OA. Clear staining for cadherin 11 was also observed in lung tissues from RA-associated IP and idiopathic IP patients, but was very limited in normal lung tissue. Cadherin 11 staining correlated strongly with the degree of inflammatory infiltration of the tissue, as well as with the C-reactive protein level and the erythrocyte sedimentation rate in RA patients. In vitro, cadherin 11 expression by FLS was consistently up-regulated by tumor necrosis factor ␣ (TNF␣) at the protein, but not the messenger RNA, level. Cadherin 11 staining in vivo was strongly down-regulated by prednisone treatment in RA patients and by TNF␣ blockade in SpA patients.Conclusion. Cadherin 11 expression is regulated by mediators of inflammation, such as TNF␣. Since cadherin 11 plays an important role in cartilage destruction in experimental arthritis, down-modulation of cadherin 11 by potent antiinflammatory therapies in humans with arthritis may contribute to halting cartilage damage.The synovial membrane, which encloses the joint cavity, consists of an intimal lining layer supported by the loose connective tissue of the synovial sublining. Under physiologic conditions, the intimal lining is composed of a few cell layers of apposing fibroblast-like synoviocytes (FLS) and CD68ϩ macrophage-like cells. In chronic arthritis, the intimal lining layer thickens to

Cadherin-11 regulates fibroblast inflammation

“…Furthermore, a recent study showed that TNF-α increased cad-11 expression on synovial fibroblasts in vitro and found that the expression level of cad-11 may be higher in inflammatory compared with normal synovium in vivo (39), which may further contribute the synergistic effects of cad-11 with TNF-α on IL-6 production in patients. In addition to increased expression of cad-11 on synovial fibroblasts, activation of JNK was increased when cells were stimulated with cad-11 in the presence of TNF-α (Fig.…”

“…Because cad-11 has also been reported to be up-regulated on fibroblasts in other inflamed tissues such as skin (49) and lung (39), it is likely that cad-11 plays a similar role in fibroblastmediated inflammation in these and other tissues as well.…”

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

“…Of particular interest in this context is the fact that IL-1␣ A final important issue is how the distinct inflammatory milieu in the inflamed SpA joint translates into differences in phenotype and disease progression as compared with that in the inflamed RA joint. In RA, TNF␣ and IL-1␤ are important drivers of bone and cartilage damage (46)(47)(48)(49)(50). Although lower levels of these cytokines in the inflamed SpA joint may contribute to the preservation of tissue integrity, no clear differences in downstream destructive processes have yet been demonstrated between SpA and RA (34,46,51).…”

“…In RA, TNF␣ and IL-1␤ are important drivers of bone and cartilage damage (46)(47)(48)(49)(50). Although lower levels of these cytokines in the inflamed SpA joint may contribute to the preservation of tissue integrity, no clear differences in downstream destructive processes have yet been demonstrated between SpA and RA (34,46,51). Alternatively, rather than protecting from tissue destruction, low levels of M1-derived cytokines in SpA may contribute by allowing tissue repair (50,52).…”

Role of Bone Marrow in the Pathogenesis of Rheumatoid Arthritis

“…It should be pointed out that generation of FLC from RA bone marrow CD34+ cells or pDC was correlated with MMP-1 levels in culture supernatants (Hirohata et al,2001;Hirohata et al,2011). On the other hand, it has been demonstrated that cadherin-11 is abundantly expressed in type B synoviocytes (Chang et al,2010) compared with lung or dermal fibroblasts (Vandooren et al,2008). Accordingly, the FLC induced from RA and OA bone marrow pDC expressed comparable amounts of cadherin-11 mRNA to RA and OA synovial FLC (Hirohata et al,2011).…”