Osteoarthritis: at the crossroads of metabolism and inflammation

This thesis aimed to investigate how metabolic overload contributes to the pathophysiology of knee OA. We explored the role of these independent yet intertwined processes using state-of-the-art lipidomic and cellular approaches in mouse models of diet-induced OA. Chapter 2 presents an overview of twelve preclinical studies in which mice received various high-caloric diets at variable duration. From this comprehensive overview we deduced that diet-induced metabolic overload per se does not necessarily lead to aggravated articular cartilage degradation. The studies that demonstrated aggravated cartilage degradation were performed in mouse strains transgenic for human proteins involved either in inflammation or lipoprotein metabolism. We suggest that an additional trigger, other than high-caloric feeding alone, is necessary to evoke metabolic OA.
To evaluate whether nutritional fat could indeed aggravate OA progression, low- and high-fat feeding was combined with a mild mechanical stressor (Chapter 3). OA onset was induced by microsurgical destabilization of the medial meniscus (DMM) in C57BL/6J mice. High-fat diet (HFD) feeding increased OA severity in this model and our findings point to a role for both lipid dysregulation and monocyte activation in disease pathogenesis. Based on these results, we suggest that these systemic factors might contribute to a diet-induced proinflammatory environment that enables aggravation of cartilage degeneration.
To unravel the effects of a dysregulated lipid metabolism on the inflammatory state, we studied the development of metabolic inflammation both locally and systemically. In Chapter 4, we focussed on the inflammatory status of the infrapatellar fat pad (IFP) during OA progression. The most pronounced inflammation and a trend towards increased fibrosis was found in IFP of mice that received a HFD on top of a microsurgical trigger (DMM). These data suggest that HFD provides a priming effect on the IFP.
Next, we addressed innate immune system involvement in the development of diet-induced OA. We provided male mice from a human C-reactive protein (hCRP) knock-in strain with an HFD for 38 weeks (Chapter 5). We demonstrated that hCRP-transgenic mice developed more severe OA compared with their wild-type controls under the same HFD regimen. This finding implicates CRP as an independent trigger to aggravate HFD-induced OA development. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process.
To expand on the outcomes of Chapters 3 and 5, in Chapter 6 we assessed the contribution of elevated plasma cholesterol levels to the severity of diet-induced OA. Cholesterol is involved in lipid metabolism as well as inflammation and is described to aggravate OA progression. We observed insignificant effects of therapeutic cholesterol-lowering on OA features and suggest that cholesterol-lowering treatments alone are probably not effective in preventing progression of pre-existent OA. Possibly, absence of inflammation in this model might explain the reduced effectiveness of cholesterol lowering, which bears implications for the clinical setting.
In Chapter 7, the general discussion, we discuss the implications of findings described in this thesis and propose to view the metabolic OA subtype as a whole-body disease instead of a whole-joint disease.