Synovial macrophages promote TGF-ß signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low-density lipoproteins.

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-ß 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-ß 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.

Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats differ in their recovery from stress-induced ulcers.

The aim of the present study was to investigate the effects of restraint-in-water-stress on gastric ulcerations in two fundamentally different types of animals: the apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats. APO-SUS and APO-UNSUS do not only differ in their susceptibility to the dopamine agonist apomorphine, but also in stress-induced release of mesolimbic dopamine and corticosterone. All three factors are known to either predict or be involved in gastric ulceration. The results showed that immediately after the stressor the ulcerations in APO-SUS and APO-UNSUS rats were not line-specific. On the contrary, the recovery from gastric ulceration varied between both types of rat: APO-SUS rats did not show any sign of recovery after 6 hours whereas APO-UNSUS rats significantly recovered during the period of 0-6 hr after the stressor. It is hypothesised that this difference is due to the fact that APO-UNSUS rats are characterised by a less and shorter-lasting stress-induced increase of corticosterone. This study provides evidence that the pathological effects of exposure to stressors significantly differ between APO-SUS and APO-UNSUS rats and that genetic factors may direct the process of recovering from ulcers.