High-fat dietary consumption promotes disease progression in a surgical joint destabilisation murine model of osteoarthritis: role of systemic eicosanoids and circulating monocytes

Abstract

Background In this study we investigated the contribution of high-fat diet-induced metabolic overload to osteoarthritis (OA) progression originally caused by mild mechanical trauma to the mouse knee joint. We hypothesized that metabolic stress would induce a proinflammatory environment by altering systemic lipid levels and immune cell populations. Methods Twelve-week-old male C57BL/6J mice (n=20) were given a low-fat diet (LFD, 10%kcal from fat) or high-fat diet (HFD, 45%kcal from fat) for 18 weeks. OA was initiated by transecting the medial meniscotibial ligament of the right knee joint at t=10 weeks. OA severity and changes in M1/M2 polarization of synovial macrophage populations were determined in serial coronal FFPE-mounted sections. Eicosanoid levels and monocyte populations were evaluated before and after ligament transection. Results Diet-induced metabolic stress assessed by body weight, systemic cholesterol levels, and insulin resistance index was significantly higher in HFD mice. This group also showed increased cartilage damage, synovitis, and osteophyte formation compared with LFD controls. High-fat feeding elevated systemic arachidonic acid levels, which mainly resulted in increased levels of its cytochrome P450-catalysed diol metabolites 5,6-dihydroxyeicosatrienoic acid (DHET) and 8,9-DHET. High-fat feeding also triggered an increase in pro-inflammatory intermediate CD43++Ly6Cint monocytes after ligament resection. Ligament resection in addition to high-fat feeding induced increased expression of the activation marker CD11c selectively on non-classical CD43++Ly6Clow monocytes. No significant changes in synovial macrophage polarization were observed. Conclusions Metabolic stress resulted in a proinflammatory environment and aggravated injury-induced OA progression. Our results suggest that a CYP450-focused eicosanoid metabolism and activated circulating monocytes may be drivers of this metabolic stress-induced OA progression, contributing to the mechanistic understanding and potentially serving as future diagnostic and prognostic biomarkers for metabolic OA.

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

“…In patients with OA, it was found that intermediate monocytes are enriched in the synovial fluid compared to the circulation and that higher levels of intermediate monocytes correlate with worse KOOS and WOMAC function scores [ 123 ]. In mice fed a high-fat diet, increased monocyte activation was seen in addition to increased joint damage, with long-term feeding showing increased levels of systemic intermediate monocytes [ 124 ]. Increased intermediate monocyte levels could influence OA development via differentiation to pro-inflammatory macrophages in the synovium and IPFP, but also via differentiation to osteoclasts in the subchondral bone [ 125 ].…”