Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis

Abstract

An increasing number of studies show how changes in intracellular metabolic pathways alter tumor and immune cell function. However, little information about metabolic changes in other cell types, including synovial fibroblasts, is available. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are the most common cell type at the pannus-cartilage junction and contribute to joint destruction through their production of cytokines, chemokines, and matrix-degrading molecules and by migrating and invading joint cartilage. In this review, we show that these cells differ from healthy synovial fibroblasts, not only in their marker expression, proto-oncogene expression, or their epigenetic changes, but also in their intracellular metabolism. These metabolic changes must occur due to the stressful microenvironment of inflamed tissues, where concentrations of crucial nutrients such as glucose, glutamine, and oxygen are spatially and temporally heterogeneous. In addition, these metabolic changes will increase metabolite exchange between fibroblast and other synovial cells, which can potentially be activated. Glucose and phospholipid metabolism as well as bioactive lipids, including sphingosine-1-phosphate and lysophosphatidic acid, among others, are involved in FLS activation. These metabolic changes likely contribute to FLS involvement in aspects of immune response initiation or abnormal immune responses and strongly contribute to joint destruction.

Keywords: Bioactive lipids; FLS; Fibroblast-like synovicyte; Glycolysis; Metabolism.

Fig. 1

Representative hematoxylin and eosin staining of (a) normal synovium lining, (b) rheumatoid arthritis synovium showing lining hypertrophy, (c) normal bone/synovium interphase in normal murine ankle, (d) arthritic bone/synovium interphase in arthritis murine ankle. Vertical lines show thickness of synovial lining. Arrows indicate pannus that migrated into the bone. Scale bars repressent 100μm

Fig. 2

Main mechanisms of FLS activation. The pro-inflammatory environment in RA joints, including high levels of cytokines, growth factors, and infiltrating inflammatory cells, strongly activates FLS. Other stimuli, such as danger-associated molecular patterns (DAMPs), microparticles, activation of calcium channels or stimulation through synovial nerves, complement, and antibodies are also important triggers of inflammatory signaling pathways, metabolic shifts, and epigenetic changes. AA amino acids, PI3K phosphoinositide 3-kinase, TLR Toll-like receptor

Fig. 3

Metabolic alterations involved in activated cells. Activated cells take up large amounts of glucose and glutamine and divert them to the pentose phosphate pathway (PPP) and lipid biosynthesis, respectively. Coupled to increased uptake of glycine, serine, and branched chain amino acids (leucine, isoleucine, and valine), which are required for protein synthesis, this generates sufficient building blocks (nucleic acids, proteins, and membranes) for proliferation. The increased generation of reactive oxygen species requires appropriate levels of antioxidants, most of which originate from the PPP. These metabolic changes generate bioactive metabolites that are secreted, and that also contribute to cell activation. Abbreviations: 3-PG 3-phosphoglycerate, A-KG α-ketoglutarate, CoA coenzyme A, G6P glucose-6-phosphate, LPA lysophosphatidic acid, L-AA L-amino acids, R5P ribose-5-phosphate, S1P sphingosine-1-phosphate, PPP pentose phosphate pathway