Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis

Abstract

Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

“…Macrophages, known as the classically activated pro‐inflammatory M1 phenotype and the alternatively activated anti‐inflammatory M2 phenotype, play a major role in joint inflammation and subsequent tissue damage in RA . To verify the effect of CB2 on macrophage polarization during the inflammation of CIA, we performed double immunostaining of F4/80 and iNOS or CD206.…”

“…The activation of CB2 inhibits the inflammatory response in the CIA mice by switching M1 macrophages to M2 macrophages. Macrophages are considered to serve essential functions in RA pathogenesis because they are the main producers of pro‐inflammatory cytokines that promote inflammation . The number of synovial macrophages is correlated with the clinical disease activity, and selective macrophage depletion has a strong anti‐inflammatory effect in animal models of arthritis .…”

Kaempferitrin inhibits proliferation, induces apoptosis, and ameliorates inflammation in human rheumatoid arthritis fibroblast‐like synoviocytes

“…Accumulating data have proven that FLS are crucial in the development of RA. The dysregulated proliferation, as well as highly invasive and migratory abilities of FLS in RA joints are the main hallmarks of RA (Doody et al, ; Falconer et al, ). Activated FLS can produce several pro‐inflammatory cytokines and MMPs, which play pivotal roles in the development of RA (Doody et al, ).…”

Proprotein convertases: Key players in inflammation-related malignancies and metastasis

“…Further studies revealed that these processes were linked to PC substrates blockade such as Notch receptor [9]. Furthermore, following inflammatory stimulus, the latter interacts first with cell surface through the proteoglycan layer that includes different classes of adhesion molecules directly connected the ECM [2]. The adhesion capacity and/or the expression of these adhesion molecules are also regulated by the PCs, suggesting the direct participation of the PCs in the initial and late interaction of targeted cells with pathogenic stimulus.…”

“…Indeed, inflammation is linked to increased activation and migration/ invasion of circulating immune cells including lymphocytes and macrophages that release inflammatory mediators (cytokines and cyclooxygenase derivatives). The persistent accumulation of these mediators causes various pathologies including obesity, rheumatoid arthritis, diabetes, cardiovascular disease, inflammatory bowel syndrome and cancer [1][2][3].…”