Background/Purpose: Pathologic bone resorption in rheumatoid arthritis (RA) is mediated by multinucleated osteoclasts (OC) at the bone-pannus junction. OC differentiation (OCgenesis) is dependent on a number of signals that promote cell fusion, formation of specific organelles and the development of a ruffled border. Dendritic Cell-Specific Transmembrane Protein (DC-STAMP), is upregulated in monocytes at early stages of OCgenesis and is required for cell-cell fusion. DC-STAMP^-/-mice develop mild osteopetrosis, due to the presence of mononuclear OC with limited capacity to resorb bone. The role of DC-STAMP in the induction of joint inflammation and pathologic bone resorption has not been examined. Therefore, we determine whether the absence of DC-STAMP ameliorates joint inflammation and bone damage in the TNF transgenic murine arthritis model.

Methods: Four experimental groups of 7-month old C57BL/6, DC-STAMP^-/-, TNF-Tg and DC-STAMP^-/- x TNF-Tg mice were generated. The presence of arthritis was determined by visual examination along with recording of grip strength, and ankle width. We analyzed the impact of DCSTAMP deficiency on bone architecture with mCT-scan analysis. The extent of tibial bone resorption was determined by the area occupied by OC in bone sections. Serum cytokines were quantitated by multiplex assay and the accumulation of inflammatory cells in bone sections was quantitated by immunofluorescence microscopy.

Results: DC-STAMP^-/-x TNF-Tg mice had a 2.5-fold decrease in ankle thickness from week 28 to 49 of age, compared to age-matched TNF-Tg mice (p<0.0001), and was comparable to that of C57BL/6 and DC-STAMP^-/- mice. Notably, DC-STAMP^-/- x TNF Tg mice had a significantly smaller TRAP⁺area in the tibia, compared to the TRAP⁺ area in the tibia of TNF-Tg mice (1.05 ±0.1 vs 17.3 ±0.6, p=0.0001). Consistent with the reduction in OC in the tibia, we found a four-fold reduction in bone resorption by OCs in DCSTAMP^-/- x TNF-Tg mice, compared to TNF-Tg mice (0.053 ±0.05 vs. 0.21 ±0.005, p=0.002). Accumulation of inflammatory cells in the synovia and systemic levels of proinflammatory molecules were markedly reduced in DC-STAMP^-/- x TNF-Tg mice (IL-α: 80 pg/ml, 3-fold decrease, p=0.001; TNF-α: 20 pg/ml, 30-fold decrease, p=0.04 and MCP1: 56 pg/ml, 3-fold decrease, p=0.04). In contrast, macrophage infiltration was abundant in the synovial tissue from TNF-Tg mice and correlated with the significantly higher levels of MCP1 (170 pg/ml), a chemokine that attracts macrophages into inflamed tissues.

Conclusion: In addition to the well-known role of DC-STAMP in cell-cell fusion, we found that it is required for progressive development of synovitis and joint damage in the setting of TNF mediated arthritis. Apparently, DC-STAMP modulates synovitis and joint damage through regulation of signaling events that promote differentiation and activation of monocytes and possibly other immune cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dendritic-cell-specific-transmembrane-protein-dc-stamp-regulates-inflammation-and-joint-damage-in-the-tnf-tg-mouse-model/