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Recent research from Radboudumc provides new insights into the role of macrophages in osteoarthritis (OA), revealing a mixed phenotype that may explain the simultaneous tissue breakdown and buildup observed in the disease. This study, published in Rheumatology (Oxford), could inform future therapeutic strategies targeting inflammation and tissue remodeling in OA patients.
Osteoarthritis (OA) is the most prevalent joint disease, affecting about 1.5 million individuals in the Netherlands. Patients often experience pain and disability, with a long treatment process and a decreased quality of life as a result, together posing a huge personal and societal burden. As there is no cure or disease-modifying treatment available, research on underlying disease processes is important.
Pathologically, osteoarthritis is characterized by concurrent breakdown processes, such as degradation of cartilage, and excessive buildup processes, such as scarring of the synovial tissue that lines the joint cavity and bone formation at wrong places. Inflammation of the synovium is often present in osteoarthritis patients and is associated with disease progression. This inflammation is relatively low grade and mainly restricted to the innate immune system. Particularly macrophages are crucial cells orchestrating this inflammation.
As part of the research group led by Peter van der Kraan, researchers Nienke van Kooten and Martijn van den Bosch investigated the phenotype of macrophages isolated from the synovial tissue of osteoarthritis patients to see whether these cells could explain the counterintuitive combination of simultaneous breakdown and excessing buildup processes.
Their data showed that macrophages were indeed the most frequent immune cell type found in the synovium. They mainly presented with a M2-like, anti-inflammatory, phenotype. However, the majority of cells also showed marker expression representative of more pro-inflammatory macrophages, indicating a mixed macrophage phenotype.
Since macrophage phenotype is strongly influenced by inflammatory factors, it was next determined whether S100A8/A9, a protein that is found to be present in high quantities throughout the course of OA and is known to affect myeloid cell phenotype, could induce the macrophage differentiation as observed in the OA patients. In an in vitro model, monocytes were differentiated towards macrophages in the presence of S100A9.
Whereas S100A8/A9 is generally considered a pro-inflammatory factor, it clearly induced markers indicative of the more anti-inflammatory M2-like macrophages, although pro-inflammatory M1-like macrophage markers were also found. Furthermore, on the level of cytokine production S100A9 exposure modestly increased expression and secretion of pro-inflammatory markers like IL-1β and catabolic, cartilage degrading enzymes like MMPs, but also increased expression and secretion of anti-inflammatory/anabolic markers like IL-10. Additionally, S100A9 increased phagocytic activity. This together indicates a dual-faced macrophage phenotype similar to the macrophages observed in osteoarthritis synovium.
In conclusion, these data show that macrophages in OA synovium predominantly present with a mixed phenotype and that S100A8/A9 induces a phenotype that resembles this. The properties of these cells could help explain the catabolic/anabolic dualism in established OA joints with low-grade inflammation and therefore support future research on inflammation in OA.
This research is part of Radboudumc Research Program: Chronic inflammatory diseases: from disease characteristics to precision medicine
About the publication
van Kooten NJT, Blom AB, Teunissen van Manen IJ, Theeuwes WF, Roth J, Gorris MAJ, Walgreen B, Sloetjes AW, Helsen MM, Vitters EL, van Lent PLEM, Koëter S, van der Kraan PM, Vogl T, van den Bosch MHJ. S100A8/A9 drives monocytes towards M2-like macrophage differentiation and associates with M2-like macrophages in osteoarthritic synovium. Rheumatology (Oxford). 2025 Jan 1;64(1):332-343. doi: 10.1093/rheumatology/keae020. PMID: 38216750; PMCID: PMC11701306.
