Pro-resolving lipid mediator ameliorates obesity induced osteoarthritis by regulating synovial macrophage polarisation

Abstract

Non-resolved persistent macrophage-mediated synovial inflammation is considered as one of the main drivers of both the establishment and progression of obesity-associated osteoarthritis (OA). Herein, we used clodronate-loaded liposomes (CL) to locally deplete macrophages in the synovial joints to examine the role of macrophages in the progression of obesity-induced OA. Furthermore, resolvin D1 (RvD1), a unique family of pro-resolving lipid mediator derived from the omega-3 polyunsaturated fatty acid, have shown marked potency in changing the pro-inflammatory behaviour of the macrophages. We sought to determine whether RvD1 administration ameliorates obesity-induced OA by resolving macrophage-mediated synovitis. Therapeutic properties of RvD1 and macrophage depletion (CL) were tested for its ability to slow post-traumatic OA (PTOA) in obese mice models. PTOA was induced in C57Bl/6 mice fed with high-fat diet (HFD) by surgically destabilising the meniscus. Firstly, CL treatment showed beneficial effects in reducing synovitis and cartilage destruction in obese mice with PTOA. In vitro treatment with RvD1 decreased the levels of pro-inflammatory markers in CD14+ human macrophages. Furthermore, intra-articular treatment with RvD1 diminishes the progression of OA in the knee joint from mice as follows: (a) decreases macrophages infiltration in synovium, (b) reduces the number of pro-inflammatory macrophages in synovium and (c) improves the severity of synovitis and cartilage degradation. Thus, our results provide new evidence for the potential targeting of macrophages in the treatment of obesity-induced OA.

Chondroprotective Factors in Osteoarthritis: a Joint Affair

“…Lipid mediators are not only pro-inflammatory like eicosanoids but also drive inflammation resolution. Resolvin D1 inhibits synovial macrophage-driven cartilage damage [ 112 ], and the resolvin precursor 17-HDHA is associated with pain but not cartilage loss [ 113 ]. These emerging targets converge on the chronic inflammatory pathways that underlie OA.…”

Cartilage tissue engineering for obesity-induced osteoarthritis: Physiology, challenges, and future prospects

“…Growing evidence indicates that obesity contributes to worse existing OA or induces the development of pathological changes by causing inflammation [ 20 ]. Although “inflammation is a beneficial process, designed to contain and eradicate threats to the host organism”, the persistent inflammation-induced alterations in joint homeostasis in obesity-induced OA potentially suppress the resolution of inflammation and lead to failure of tissue regeneration [ 21 ].…”

“…Schelbergen et al show that S100A/S100A9 induce over-expression and activation of matrix metalloproteinase, leading to cartilage matrix remodeling and osteophyte formation in experimental OA with high synovial activation [ 37 ]. Moreover, in vivo and in vitro studies indicate that the balance between pro- and anti-inflammatory macrophage production has a significant impact on the development of synovial joint inflammation in obesity-induced OA [ 9 , 20 ]. This subject is covered in more detail in the section on “localised joint inflammation."…”

“…It has also been shown that obese mice fed high-fat diets rich in pro-inflammatory saturated fatty acid (FAs), and ω-6 FAs showed cartilage degradation, alteration in bone structure, and synovitis as well as increased infiltration of activated macrophages into synovial tissue [ 68 ]. In addition, localised depletion of synovial macrophages using clodronate liposome resulted in a reduction of cartilage damage and synovitis in the diet-induced obesity mouse model [ 20 ]. These findings suggest that macrophage-mediated synovitis as drivers of OA symptoms and pathology in obesity.…”

“…Several lines of evidence implicate an imbalance between M1/M2 macrophages in the pathogenesis of obesity-induced OA. We have demonstrated that synovial macrophages in mice with obesity-induced OA were predominantly polarised to the pro-inflammatory phenotype, while M2 macrophages were observed in inflamed synovium [ 20 ]. This skewing to the M1 phenotype in synovium was accompanied by the worsening of OA [ 69 ].…”