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

OBJECTIVE:

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.

DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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: W de Munter, E J W Geven, A B Blom, B Walgreen, M M A Helsen, L A B Joosten, J Roth, T Vogl, F A J van de Loo, M I Koenders, W B van den Berg, P M van der Kraan, P L E M van Lent
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 25 Issue 1 Pg. 118-127 (01 2017) ISSN: 1522-9653 [Electronic] England
• PMID: 27514996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Calgranulin A
• Calgranulin B
• Lipoproteins, LDL
• Transforming Growth Factor beta

Topics

• Animals
• Calgranulin A (metabolism)
• Calgranulin B (metabolism)
• Humans
• Injections, Intra-Articular
• Lipoproteins, LDL (administration & dosage, pharmacology)
• Macrophages (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Osteoarthritis (metabolism)
• Synovial Fluid (cytology, physiology)
• Transforming Growth Factor beta (physiology)