title: Synovial macrophages promote TGF-β signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low-density lipoproteins.
abstract: Low-density lipoproteins (LDL) in inflamed synovium is oxidized and taken-up by synoviocytes. In this study, we investigate whether direct injection of oxidized LDL (oxLDL) into a normal murine knee joint induces joint pathology and whether synovial macrophages are involved in that process.
  
  
  
  Synovium was obtained from end-stage osteoarthritis (OA) patients in order to analyze LDL-uptake. Murine knee joints were injected five consecutive days with oxLDL, LDL, or vehicle (phosphate buffered saline (PBS)). This procedure was repeated in mice depleted of synovial macrophages by intra-articular injection of clodronate liposomes 7 days prior to the consecutive injections. Joint pathology was investigated by immunohistochemistry, flow cytometry (FCM) and synovial RNA expression and protein production.
  
  
  
  Synovial tissue of OA patients showed extensive accumulation of apolipoprotein B. Multiple injections of oxLDL in murine knee joints significantly increased TGF-β activity in synovial wash-outs, but did not induce catabolic or inflammatory processes. In contrast, repeated injections of oxLDL in macrophage-depleted knee joints led to increased synovial thickening in combination with significantly upregulated protein and RNA levels of CCL2 and CCL3. FCM-analyses revealed increased presence of monocytes and neutrophils in the synovium, which was confirmed by immunohistochemistry. Also protein levels of S100A8/A9 were significantly increased in synovial wash-outs of oxLDL-injected joints, as was expression of aggrecanase-induced neo-epitopes. Interestingly, no raise in TGF-β concentrations was measured in macrophage-depleted joints.
  
  
  
  OxLDL can affect joint pathology, since synovial macrophages promote anabolic processes after oxLDL injections. In absence of synovial macrophages, however, oxLDL induces production of pro-inflammatory mediators and aggrecanase activity combined with increased influx of monocytes and neutrophils.
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Wouter.deMunter@radboudumc.nl.
authors: W
authors: W
authors: de Munter
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Edwin.Geven@radboudumc.nl.
authors: E J W
authors: EJ
authors: Geven
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Arjen.Blom@radboudumc.nl.
authors: A B
authors: AB
authors: Blom
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Birgitte.Walgreen@radboudumc.nl.
authors: B
authors: B
authors: Walgreen
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Monique.Helsen@radboudumc.nl.
authors: M M A
authors: MM
authors: Helsen
authors: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Leo.Joosten@radboudumc.nl.
authors: L A B
authors: LA
authors: Joosten
authors: Institute of Immunology, University of Muenster, Muenster, Germany. Electronic address: rothj@uni-muenster.de.
authors: J
authors: J
authors: Roth
authors: Institute of Immunology, University of Muenster, Muenster, Germany. Electronic address: vogl@uni-muenster.de.
authors: T
authors: T
authors: Vogl
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Fons.vandeLoo@radboudumc.nl.
authors: F A J
authors: FA
authors: van de Loo
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Marije.Koenders@radboudumc.nl.
authors: M I
authors: MI
authors: Koenders
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Wim.vandenBerg@radboudumc.nl.
authors: W B
authors: WB
authors: van den Berg
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Peter.vanderKraan@radboudumc.nl.
authors: P M
authors: PM
authors: van der Kraan
authors: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Peter.vanLent@radboudumc.nl.
authors: P L E M
authors: PL
authors: van Lent
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D006801:Humans; D007270:Injections, Intra-Articular; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D008077:Lipoproteins, LDL; D016212:Transforming Growth Factor beta
keywords: Inflammation; Low-density lipoprotein; Osteoarthritis; Oxidized LDL; S100 proteins