TLR4 Promotes and DAP12 Limits Obesity-Induced Osteoarthritis in Aged Female Mice.

Evangelia Kalaitzoglou,Yao Fu,Mary Beth Humphrey,Jacquelyn C Herron,Josiah M Flaming,Adrian Filiberti,Timothy M Griffin,Yanqing Hu,Elise L Donovan,Erika Barboza Prado Lopes

doi:10.1002/jbm4.10079

Abstract

ABSTRACTAging and female sex are the strongest risk factors for nontraumatic osteoarthritis (OA); whereas obesity is a modifiable risk factor accelerating OA. Prior studies indicate that the innate immune receptor toll‐like receptor 4 (TLR4) mediates obesity‐induced metabolic inflammation and cartilage catabolism via recognition of damage‐associated molecular patterns and is increased with aging in OA joints. TLR4 responses are limited by innate immunoreceptor adapter protein DNAX‐activating protein of 12kDA (DAP12). We undertook this study to test the hypothesis that TLR4 promotes, whereas DAP12 limits, obesity‐accelerated OA in aged female mice. We fed 13‐ to 15‐month‐old female WT, TLR4 KO, and DAP12 KO mice a high‐fat diet (HFD) or a control diet for 12 weeks, and changes in body composition, glucose tolerance, serum cytokines, and insulin levels were compared. Knee OA was evaluated by histopathology and μCT. Infrapatellar fat pads (IFPs) were analyzed by histomorphometry and F4/80+ crown‐like structures were quantified. IFPs and synovium gene expression were analyzed using a targeted insulin resistance and inflammation array. All HFD‐treated mice became obese, but only WT and TLR4 KO mice developed glucose intolerance. HFD induced cartilage catabolism in WT and DAP12 KO female mice, but not in TLR4 KO mice. Gene‐expression analysis of IFPs and synovium showed significant differences in insulin signaling, adipokines, and inflammation between genotypes and diets. Unlike young mice, systemic inflammation was not induced by HFD in the older female mice independent of genotype. Our findings support the conclusion that TLR4 promotes and DAP12 limits HFD‐induced cartilage catabolism in middle‐aged female mice. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Highlights

Osteoarthritis (OA) is the most prevalent form of arthritis, affecting millions of people worldwide
Toll-like receptor 4 (TLR4) activation induces nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) signaling and proinflammatory cytokine production, which are both upregulated in OA joint tissues.[12] mice lacking TLR4 are partially protected against insulin resistance and adipose tissue inflammation caused by high-fat diet (HFD)-induced obesity.[13,14] This
Obesity increases the incidence of knee OA in a female sex and age-dependent manner in people,(3) most preclinical animal models of diet-induced obesity and OA have initiated HFD in weanling or young male mice.[27]. Our study is unique in several ways

Summary

Introduction

Osteoarthritis (OA) is the most prevalent form of arthritis, affecting millions of people worldwide. TLR4 activation induces nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) signaling and proinflammatory cytokine production, which are both upregulated in OA joint tissues.[12] mice lacking TLR4 are partially protected against insulin resistance and adipose tissue inflammation caused by HFD-induced obesity.[13,14] This. We tested the hypothesis that TLR4 and DAP12 regulate HFD-accelerated knee OA in aged female mice. We selected aged female mice for this study based on the higher prevalence of knee OA in older women and the importance of age in establishing physiologic mechanisms of OA pathogenesis. By comparing HFD-induced changes in systemic and local joint inflammation in animal models that modulate TLR4 signaling positively and negatively, we provide new insight into how TLR4-dependent pathways are activated and regulated in obesity, aging, and OA

Methods

Results

Conclusion