Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

Abstract

Objective. We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes.Methods. Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes.Results. Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity.Conclusion. These results suggest that chondrocytes play a role in the development of RA via TMEM147mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

How COVID-19 induces cytokine storm with high mortality

“…Indeed, activation tends to occur more easily in tissue-specific non-immune cells such as tracheal basement cells, synovial fibroblasts, keratinocytes, kidney tubule cells, and chondrocytes. Therefore, through the IL-6 amplifier, these cells could regulate several tissue specific-inflammatory diseases [56][57][58][59][60]. Furthermore, activation of the IL-6 amplifier depends on various environmental and genetic factors.…”

“…The IL-6 amplifier is a hyper NF-κB activation machinery in non-immune cells induced by the simultaneous activation of NF-κB and STAT3. It induces a massive and sustained production of NF-κB target genes, including IL-6, chemokines, and growth factors, which is critical for the development of various disease models including lung transplantation, rheumatoid arthritis, and multiple sclerosis [ 56 – 60 ]. Furthermore, we have shown that the co-activation of NF-κB and STAT3, which is evidence of activation of the amplifier, is observed in clinical specimens from patients with inflammatory diseases [ 56 , 61 ].…”

Construction of CII-Specific CAR-T to Explore the Cytokine Cascades Between Cartilage-Reactive T Cells and Chondrocytes

“…An important point to note is that cartilage participates in both inflammatory and bone destruction phases (34). Chondrocytes are only resident cells in the cartilage, which not only act as target cells of inflammatory mediators, but also serve as effector cells and play an important role in cytokine cascades (15,(35)(36)(37)(38). Insights into the cascades between chondrocytes and cartilagereactive T cells could be helpful to find new biological markers and therapeutic targets of inflammatory arthritis.…”

“…Unlike a number of other cytokines, IL-6 can activate cells through both membrane-bound (IL-6R) and soluble receptors (sIL-6R), thus widening the number of cell types responsive to this cytokine (48)(49)(50)(51). IL-6-mediated inflammation amplifier was reported as a key molecular mechanism in chronic inflammation (15,52,53), which triggers a vicious circle of escalating RA disease activity (51,54,55). IL-6 plus TNF-a or IL-6 plus IL-17 can trigger IL-6 amplifier, leading to positive feedback for IL-6 signaling (15).…”

“…Under pathological conditions, T cells behave as a hub, in which B cells, dendritic cells (DCs), and tissue-resident cells can interact with T cells to intensify the process of RA (11)(12)(13)(14). Recent studies have shown that chondrocytes play an important role in amplifying inflammatory responses during RA development (15). Exploration of the amplifying inflammatory responses produced by cartilage-reactive T cells and chondrocytes might help reveal the effective clinical interventions and treatment targets.…”