Understanding fat metabolism could lead to new arthritis treatments
Common anti-inflammatory drugs such as Ibuprofen act by blocking certain chemical pathways that cause arthritis pain. However, they are not a cure and must be used lifelong, so scientists are using a novel approach, studying the influence of metabolism on these incurable diseases. “Lipids (fatty compounds) have been underestimated in general, but in arthritis they are a driver of inflammation, having pro- and anti-inflammatory effects,” explains ArthritisHeal project coordinator Martin Giera, head of the Metabolomics Group at the Center for Proteomics and Metabolomics, Leiden University Medical Center, the Netherlands. “So, we looked at the influence of fats on the disease progression to see what role lipid metabolism plays, and whether understanding this can lead to potential therapeutic access into diseases such as rheumatoid arthritis and osteoarthritis,” says Giera “The idea is to have a different approach to treatment – such as normalising metabolism to restore a biological system that is out of balance – and thereby cure people, rather than making them dependent on lifelong suppression.” The project, with the support of the Marie Skłodowska-Curie Actions programme, involved two dozen early-stage and senior researchers, from fundamental scientists and researchers working on preclinical models through to clinicians working with patients.
Using biomarkers to understand the role of lipids
A number of biomarkers for lipids were tested using different analytical platforms. “We wanted to know if there is a lipid signature of rheumatoid arthritis and osteoarthritis and if they can be used as biomarkers,” Giera says. For osteoarthritis, lipid signatures were found in the form of odd-chain fatty acids. “That surprised me a lot, because that’s a specific cell type of the joint,” Giera explains, adding “these odd-chain fatty acids are thought to be mainly of microbial origin – coming from food intake, such as milk products.” “We’re testing the enzymes which exist in the human body, and it seems there really is a difference in these odd-chain fatty acids, which I would not have thought are made in the human body, and that can play a role as a disease descriptor or even as a disease mechanism,” Giera remarks.
Analysing lipid samples
Using advanced technologies, some 1 500 lipids are monitored from one patient sample within a single analysis. To assess these large amounts of information, the team devised bioinformatics-based visualisation methods which highlight the differences between types of cells. “Without this visualisation we would not have found it,” Giera notes, referring to the odd-chain fatty acid. Another key achievement was the standardisation of molecular lipid data generated in different labs, which is important for exchanging the data. “We needed to make sure the protocols are robust. If the outcome is different each time, we keep on reinventing the wheel,” he explains. This was particularly important during the COVID-19 pandemic as individual researchers were unable to travel between labs, even though researcher training was a key component of the project. Instead, materials and samples were transferred between labs. “The standardisation of our lipid tools and technologies can also benefit other projects and diseases,” Giera says, pointing to neurodegeneration research as an example.
New assays
New lipid assays were also developed by the project team to look into signalling in immune cells. Additionally, using flow cytometry machines (FACS) which measure the properties of single cells, novel assays were set up and aimed at predicting therapy response in arthritis patients. Lipid data is currently being analysed from samples from around 300 people that were run through different assays. “The lipid changes we find in the osteoarthritis cells are promising for future intervention, especially for osteoarthritis,” Giera notes.
Keywords
ArthritisHeal, arthritis, rheumatoid arthritis, osteoarthritis, metabolism, lipids, biomarkers
