TNF-α blockade with adalimumab restores bone metabolism in rheumatoid arthritis by regulating cytokines and inflammatory cell infiltration

ObjectiveTo investigate the mechanisms underlying the bone-sparing effects of the anti-TNF antibody adalimumab in rheumatoid arthritis (RA) by examining synovial tissue and its direct effect on osteoblasts and osteoclasts.MethodsPaired synovial biopsies from 12 patients with RA were obtained before and 8 weeks after initiation of adalimumab. Immune-cell infiltrates (CD163+ macrophages, CD3+ lymphocytes) and expression of osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL) were assessed by immunohistochemistry. In vitro, the effect of adalimumab on RANKL and OPG expression in SaOS-2 cells (± TNF-α) was evaluated by western blotting. Its effect on osteoclastogenesis and bone resorption were examined using CD14+ monocyte-derived macrophages cultured with RANKL and M-CSF.ResultsAdalimumab treatment led to a marked clinical improvement, with median DAS28 decreasing from 5.4 to 3.1. Semiquantitative analysis of synovial biopsies revealed a significant decrease in CD163+ macrophages, while CD3+ T-cells remained unchanged. The RANKL/OPG ratio decreased significantly, which was accompanied by increased OPG expression in synovial tissue. In vitro, adalimumab significantly decreased RANKL expression and the RANKL: OPG ratio in TNF-α primed SaOS-2 cells, while also modulating pro-osteoclastogenic cytokines. In osteoclast assays, adalimumab inhibited macrophage-derived osteoclast differentiation and suppressed bone resorption under both low and high RANKL conditions.ConclusionAdalimumab decreased synovial macrophage infiltration while it modulates pro-osteoclastogenic cytokines and inhibits osteoclastogenesis. These combined effects explain how TNF-α blockade ameliorates joint inflammation and prevents structural damage.