Metabolomics in rheumatic diseases: desperately seeking biomarkers

Abstract

Metabolomics enables the profiling of large numbers of small molecules in cells, tissues and biological fluids. These molecules, which include amino acids, carbohydrates, lipids, nucleotides and their metabolites, can be detected quantitatively. Metabolomic methods, often focused on the information-rich analytical techniques of NMR spectroscopy and mass spectrometry, have potential for early diagnosis, monitoring therapy and defining disease pathogenesis in many therapeutic areas, including rheumatic diseases. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanisms are being revealed and are shaping our understanding of cell biology, physiology and medicine. These pathways can potentially be targeted to diagnose and treat patients with immune-mediated diseases.

Figure 1. Overview of major metabolic pathways

Cellular metabolic pathways include synthesis of lipids, glycogen and nucleotides, glycolysis (the breakdown of carbohydrates and sugars to produce ATP and pyruvic acid) and the hexokinase pathway, which gives rise to substrates for the synthesis of glycoproteins and glycolipids. Mitochondrial oxidative phosphorylation (the Krebs cycle) is the sequence of reactions by which most living cells generate energy during the process of aerobic respiration. Glutaminolysis occurs partly in the mitochondrion and partly in the cytosol, and is an important energy source in tumour cells. CoA, coenzyme A; CTP, citrate transport protein; MPC, mitochondrial pyruvate carrier; PRPP, phosphoribosyl pyrophosphate; UDP, uridine diphosphate.

Figure 2. Metabolic alterations and signalling pathways 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 an increased uptake of glycine, serine and branched chain amino acids (leucine, isoleucine and valine), which are required for protein synthesis, this diversion 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. Numerous signalling pathways are involved in metabolic changes in activated cells^,. 3-PG, 3-phosphoglycerate; A-KG, α-ketoglutarate; AKT, protein kinase B; AMPK, AMP-activated protein kinase; CoA, coenzyme A; G6P, glucose-6-phosphate; HIF-1, hypoxia-inducible factor 1; L-AA, L-amino acid; LPA, lysophosphatidic acid; Myc, Myc proto-oncogene protein; p53, cellular tumour antigen p53; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; R5P, ribose-5-phosphate; S1P, sphingosine-1-phosphate; SREBP, sterol regulatory element-binding protein.