Activation of circulating monocytes by low-density lipoprotein-a risk factor for osteoarthritis?

Synovial macrophages are key mediators of OA pathology, and skewing of macrophage phenotype in favour of an M1-like phenotype is thought to underlie the chronicity of synovial inflammation in OA. Components of the metabolic syndrome (MetS), such as dyslipidaemia, can affect macrophage phenotype and function, which could explain the link between MetS and OA development. Recently published studies have provided novel insights into the different origins and heterogeneity of synovial macrophages. Considering these findings, we propose an important role for monocyte-derived macrophages in particular, as opposed to yolk-sac derived residential macrophages, in causing a pro-inflammatory phenotype shift. We will further explain how this can start even prior to synovial infiltration; in the circulation, monocytes can be trained by metabolic factors such as low-density lipoprotein to become extra responsive to chemokines and damage-associated molecular patterns. The concept of innate immune training has been widely studied and implicated in atherosclerosis pathology, but its involvement in OA remains uncharted territory. Finally, we evaluate the implications of these insights for targeted therapy directed to macrophages and metabolic factors.

Nox2 Deficiency Reduces Cartilage Damage and Ectopic Bone Formation in an Experimental Model for Osteoarthritis.

Osteoarthritis (OA) is a destructive disease of the joint with age and obesity being its most important risk factors. Around 50% of OA patients suffer from inflammation of the synovial joint capsule, which is characterized by increased abundance and activation of synovial macrophages that produce reactive oxygen species (ROS) via NADPH-oxidase 2 (NOX2). Both ROS and high blood levels of low-density lipoprotein (LDL) are implicated in OA pathophysiology, which may interact to form oxidized LDL (oxLDL) and thereby promote disease. Therefore, targeting NOX2 could be a viable treatment strategy for OA. Collagenase-induced OA (CiOA) was used to compare pathology between wild-type (WT) and Nox2 knockout (Nox2-/-) C57Bl/6 mice. Mice were either fed a standard diet or Western diet (WD) to study a possible interaction between NOX2-derived ROS and LDL. Synovial inflammation, cartilage damage and ectopic bone size were assessed on histology. Extracellular ROS production by macrophages was measured in vitro using the Amplex Red assay. Nox2-/- macrophages produced basal levels of ROS but were unable to increase ROS production in response to the alarmin S100A8 or the phorbol ester PMA. Interestingly, Nox2 deficiency reduced cartilage damage, synovial lining thickness and ectopic bone size, whereas these disease parameters were not affected by WD-feeding. These results suggest that NOX2-derived ROS are involved in CiOA development.