Abstract
IntroductionOsteoarthritis (OA) is associated with the metabolic syndrome, however the underlying mechanisms remain unclear. We investigated whether low density lipoprotein (LDL) accumulation leads to increased LDL uptake by synovial macrophages and affects synovial activation, cartilage destruction and enthesophyte/osteophyte formation during experimental OA in mice.MethodsLDL receptor deficient (LDLr−/−) mice and wild type (WT) controls received a cholesterol-rich or control diet for 120 days. Experimental OA was induced by intra-articular injection of collagenase twelve weeks after start of the diet. OA knee joints and synovial wash-outs were analyzed for OA-related changes. Murine bone marrow derived macrophages were stimulated with oxidized LDL (oxLDL), whereupon growth factor presence and gene expression were analyzed.ResultsA cholesterol-rich diet increased apolipoprotein B (ApoB) accumulation in synovial macrophages. Although increased LDL levels did not enhance thickening of the synovial lining, S100A8 expression within macrophages was increased in WT mice after receiving a cholesterol-rich diet, reflecting an elevated activation status. Both a cholesterol-rich diet and LDLr deficiency had no effect on cartilage damage; in contrast, ectopic bone formation was increased within joint ligaments (fold increase 6.7 and 6.1, respectively). Moreover, increased osteophyte size was found at the margins of the tibial plateau (4.4 fold increase after a cholesterol-rich diet and 5.3 fold increase in LDLr−/− mice). Synovial wash-outs of LDLr−/− mice and supernatants of macrophages stimulated with oxLDL led to increased transforming growth factor-beta (TGF-β) signaling compared to controls.ConclusionsLDL accumulation within synovial lining cells leads to increased activation of synovium and osteophyte formation in experimental OA. OxLDL uptake by macrophages activates growth factors of the TGF-superfamily.
Highlights
Osteoarthritis (OA) is associated with the metabolic syndrome, the underlying mechanisms remain unclear
Synovial wash-outs of LDLr−/− mice and supernatants of macrophages stimulated with oxidized LDL (oxLDL) led to increased transforming growth factor-beta (TGF-β) signaling compared to controls
low density lipoprotein (LDL) accumulation within synovial lining cells leads to increased activation of synovium and osteophyte formation in experimental OA
Summary
Osteoarthritis (OA) is associated with the metabolic syndrome, the underlying mechanisms remain unclear. The association of OA with metabolic syndrome has long been established but the exact mechanism remains unclear [1,2]. The idea that obesity enhances OA development solely due to increased loading [3] is obsolete and more often studies show the association between obesity and OA development in non-weight-bearing joints [4,5,6,7]. Decreased levels of high-density lipoprotein (HDL) and increased levels of low-density lipoprotein (LDL) particles are, amongst other features, part of the metabolic syndrome [8]. LDL can be oxidized in an inflammatory milieu and, high levels of LDL result in enhanced oxidized LDL (oxLDL) levels in pathological conditions where free radicals are present [13,14]. OxLDL is taken up by macrophages via scavenger receptor class A, B (CD36) and E (lectin-like oxLDL receptor-1; LOX-1), resulting in a phenotype shift into a more inflammatory cell type [15,16,17,18,19]
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