The Burden of Metabolic Syndrome on Osteoarthritic Joints

Bruce M. Dickson; Anke J. Roelofs; Justin J. Rochford; Heather M. Wilson; Cosimo De Bari


Arthritis Res Ther. 2019;21(289) 

In This Article

Macrophages as Key Effector Cells in OA

Infiltrating macrophages are key cells in the inflammatory processes. They are heterogeneous cells that exhibit remarkable plasticity, able to adopt many phenotypes and functions dependent on the microenvironmental signals they receive. Knowledge of the range of macrophage activation states and the cues that induce polarisation is far from complete, but two broad types of macrophage activation have been characterised: M1-activated macrophages are induced by pro-inflammatory stimuli, e.g. TNF-α, and have anti-microbial and cytotoxic properties that can damage tissue and rely heavily on glycolysis to meet their energy demands. By contrast, M2-activated macrophages are anti-inflammatory or reparative and use oxidative phosphorylation to provide a sustained ATP energy provision. A spectrum of activation states intermediate to these is found in infiltrating macrophages in vivo.[19]

Early evidence for macrophages playing a key role in the development of OA came from murine studies utilising liposomal clodronate to selectively ablate macrophages. Osteophyte formation in a model of collagenase-induced OA was significantly reduced by up to 84% when macrophages were ablated prior to inducing OA,[20] which was suggested to be due to the reductions in bone morphogenetic protein (BMP) 2 and 4 production by synovial lining macrophages.[20] In addition, macrophage ablation resulted in reduced levels of MMP2, MMP3, and MMP9 and decreased cartilage breakdown.[21] These experiments indicate the importance of macrophages in the disease process.

Activated macrophages have since been shown to be directly involved in the development of synovitis in human OA as visualised by etarfolatide-enhanced single-photon emission computed tomography-computed tomography (SPECT-CT).[22] Etarfolatide binds only to the functional form of folate receptor β, expressed abundantly on activated macrophages but not on resting macrophages. OA patients were shown to have increased numbers of activated synovial macrophages compared to healthy controls, and macrophage numbers were significantly associated with pain and joint space narrowing.[22] It was further shown that elevated soluble biomarkers, CD14 and CD163, indicative of macrophage activation, in the synovial fluid were significantly associated with increased abundance of activated synovial membrane macrophages when compared to the etarfolatide scanning results, worsening patient pain scores, and progression of OA as measured by Kellgren-Lawrence plain radiograph severity scoring.[23] Thus, these studies not only indicate that macrophages play an important role in the underlying disease process but that biomarkers of activated macrophages may be able to predict patients at high risk of disease progression.

It has been proposed that the activation and infiltration of macrophages into the synovium is brought about by an initial insult to the joint, releasing damage-associated molecular patterns (DAMPs) that are recognised by a selection of pattern recognition receptors (PRRs) expressed on macrophages (Figure 1). Macrophage recognition of DAMPs, including high-mobility group box-1 (HMGB1), S100A8 alarmins, and MMPs, leads to their activation, transcription of NF-κB, and subsequent production of pro-inflammatory mediators such as TNF, interleukin (IL)-1β, and IL-6.[24] This release of pro-inflammatory mediators leads to the activation of fibroblast-like synoviocytes and production of MMPs and disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS), which cause degradation of the cartilage through cleavage of aggrecan and other cartilage matrix proteins.[25] Meanwhile, both activated macrophages and fibroblasts release chemotactic proteins such as chemokine ligand (CCL) 2, CCL3, and CCL4 inducing infiltration of circulating monocytes and CD4+ T cells into the synovium, where the former differentiate into macrophages.[26] As well as DAMPs, metabolic intermediates can polarise macrophages to different functional states that affect their roles in OA. A study characterising the phenotype of macrophages isolated from synovial fluid showed that OA patients have a preponderance to an M1/M2 imbalance with a greater ratio of M1/M2 correlating with increasing severity of radiographic OA.[27]

Figure 1.

Chronic inflammation in osteoarthritis. a (Left) healthy synovial joint. Type A and B synoviocytes present within intimal synovial lining. The cartilage covering the articulating surface of bones. (Right) chronic inflammation within the synovial joint. b Expanded view of chronic inflammation. DAMPs released from the cartilage and synovium result in synoviocyte activation. Macrophages and CD4+ T cells infiltrate the synovium resulting in the release of pro-inflammatory mediators and chronic inflammation. The cartilage and bone are degraded and remodelled with subchondral sclerosis and osteophyte and cyst formation. (A) Fibrous capsule, (B) subintimal synovial lining, (C) intimal synovial lining, (D) type A synoviocyte, (E) type B synoviocyte, (F) synovial fluid, (G) cartilage, (H) subchondral sclerosis, (I) subchondral cyst, (J) cartilage degradation, (K) DAMP release, (L) osteophyte formation, (M) synovial hypertrophy, (N) macrophage infiltration, (O) CD4+ T cell infiltration, and (P) pro-inflammatory mediator secretion