High Fat Diet-Induced Metabolic Dysfunction Leads to Aggravation of Osteoarthritis and Inflammation of the Knee Joint in Two Different Murine Models

Purpose: Osteoarthritis is increasingly considered a metabolically driven disease, with obesity and metabolic syndrome as evident risk factors. Common features of obesity and MetS are low-grade inflammation and lipid accumulation. In previous studies we have shown that high-fat diet (HFD, 45 kcal% from fat) feeding alters lipid composition and inflammatory responses in adipose tissue and that these changes are depot-dependent. Therefore, we hypothesize that metabolic OA development is aggravated by diet-induced metabolic dysfunction through adipose inflammation. We suspect the infrapatellar fat pad (IPFP), being the major adipose depot in the knee, to be prone to HFD-induced inflammation and to play a role to the development of metabolic OA.

Methods: Diet-induced metabolic dysfunction was evaluated in two murine OA models: 1) OA was induced by destabilization of the medial meniscus (DMM) in male C57BL/6J mice fed either a low-fat diet (LFD, 10 kcal% from fat) or HFD, and 2) OA was accelerated in male ApoE3Leiden.CETP mice through prolonged feeding of a high-fat/high-cholesterol diet (HFC, 45 kcal% from fat with 1% w/w cholesterol) for 30 weeks. Right knees were harvested at end-point to assess OA severity, osteophyte formation and synovitis on Safranin O- and HE-stained histological sections according to OARSI recommendations for the mouse. Adipose inflammation was evaluated by crown-like structure (CLS) count in HPS-stained histological sections of the IPFP from the right knees. In the HFC-induced OA model, the IPFP was isolated from the left knees and cryopreserved. Left knees were imaged with (contrast enhanced-)μCT scanning (Quantum FX, PerkinElmer, USA) to identify diet-related subchondral bone changes. IPFP from left knees were used for histology and high spatial resolution (20–30ii) mass spectrometry imaging (MS imaging) analysis of inflammatory lipids. MS imaging was performed on cryosections, using MALDI-FTICR in a full scan mode (100Da–1000Da) to include the lipid profiles in the negative ionization mode.

Results: OA severity was significantly greater in the right knees of the high-fat feeding groups compared with their diet controls in both models (DMM: p=0.049, ApoE3L.CETP: p=0.034). OA severity did not correlate with body weight at end-point. Osteophyte formation and synovitis scores correlated positively with OA severity. Preliminary results confirm increased CLS counts in the IPFP of the HFD/HFC-fed mice compared with control mice in both studies. Trabecular bone volume fraction was increased in HFC-fed mice at the lateral side of the joint.

Conclusions: Our results show that HFD-induced metabolic dysfunction indeed aggravates OA progression in both a surgical and a diet-induced mouse model for OA. The lack of correlation between OA severity and body weight suggests that the metabolic dysfunction-induced inflammation may underlie metabolic OA progression. Inflammatory involvement was also confirmed through the observed association of OA severity with osteophyte formation and synovitis. Preliminary results show diet-induced inflammation in the IPFP as well, suggesting the IPFP could play a role in the development of metabolic OA.