The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains as efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage. The electronic version of this article can be found online at http://arthritis-research.com/content/2/3/189 © Current Science Ltd AP = activator protein; BST = bone marrow stromal antigen; DMARD = disease-modifying antirheumatic drug; EBER(s) = Epstein-Barr virus-encoded small nuclear RNA(s); GM-CSF = granulocyte-macrophage colony-stimulating factor; GRO = growth-related oncogene protein; HLA = human leucocyte antigen; MCP = monocyte chemoattractant protein; MIP = macrophage inflammatory protein; NF-κB = nuclear factor-κB; NO = nitric oxide; RA = rheumatoid arthritis; TGF = transforming growth factor; Th = T-helper (cell); TIMP = tissue inhibitor of metalloproteinase; TNF = tumour necrosis factor.

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Objective. To determine whether systemic elimination of macrophages by means of clodronate‐containing liposomes counteracts inflammation and joint destruction in rats with established adjuvant arthritis (AA). Methods. Rats with AA received a total of 2.7 mg of clodronate encapsulated in liposomes in 3 intravenous doses on days 10, 11, and 12 of arthritis. Phosphate buffered saline (PBS), PBS‐laden liposomes, or free clodronate were used as negative controls. Clinical, hematologic, and histopathologic signs of AA were monitored, and depletion of macrophages by clodronate‐liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MPS). Results. Clodronate‐laden liposomes led to significant, long‐term amelioration of the clinical signs of AA, a reduction in the erythrocyte sedimentation rate (ESR), and counteraction of joint destruction, not only immediately after treatment, but also for 2 weeks thereafter. Free clodronate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA. Drug‐free vesicles even aggravated the joint destruction. Clodronate‐laden liposomes did not induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the liver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. Conclusion. Clodronate‐laden liposomes induce long‐term amelioration of AA, even if administered for a brief period during the florid phase of the disease. The amelioration is paralleled by the elimination of macrophages in immunocompetent areas of the spleen and draining lymph nodes, but not locally in the SM. This suggests an influence of the treatment on the immunoregulatory rather than effector, functions of macrophages.

To reduce culture artifacts by conventional repeated passaging and long-term culture in vitro, the isolation of synovial fibroblasts (SFB) was attempted from rheumatoid arthritis (RA) synovial membranes by trypsin/collagenase digest, short-term in vitro adherence (7 days), and negative isolation using magnetobead-coupled anti-CD14 monoclonal antibodies. This method yielded highly enriched SFB (85% prolyl-4-hydroxylase+/74% Thy-1/CD90+ cells; <2% contaminating macrophages; <1% leukocytes/endothelial cells) that, in comparison with conventional fourth-passage RA-SFB, showed a markedly different phenotype and significantly lower proliferation rates upon stimulation with platelet-derived growth factor and IL-1β. This isolation method is simple and reliable, and may yield cells with features closer to the in vivo configuration of RA-SFB by avoiding extended in vitro culture.

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