Background/Purpose: Dendritic Cell (DC)-Specific Transmembrane Protein (STAMP) expressed by osteoclast precursors is required for cell-cell fusion in the formation of the osteoclast (OC) polykaryon. Genetic ablation of DC-STAMP results in mononuclear OCs and an osteopetrosis phenotype. Absence of DC-STAMP in the TNF-Tg arthritis model markedly reduces synovitis and inflammatory bone loss. OC-STAMP is another molecule required for cell-cell fusion and absence of either DC or OC-STAMP blocks multinucleation. To date, it is unknown if both molecules have redundant or cooperative functions and if their combined absence results in decreased bone damage and synovitis in inflammatory arthritis. We hypothesize that dual absence of OC-STAMP and DC-STAMP will ameliorate inflammation and bone erosion in a mouse model of acute arthritis (K/BxN).

Methods: OC-STAMP floxed mice were crossed with DC-STAMP^-/- and global B6-Cre mice to generate OC-STAMP^-/- and OC-STAMP^-/- x DC-STAMP^-/- animals. We injected WT, OC-STAMP^-/- and OC-STAMP^-/- x DC-STAMP^-/- mice with serum collected from 8-week old K/BxN mice to induce acute inflammatory arthritis. We evaluated bone loss and local inflammation by micro-CT scan and histology, respectively. We isolated CD115⁺ cells, macrophages, neutrophils, dendritic cells (DCs), T cells and differentiated M1/M2 macrophages from WT mice to assess OC-STAMP expression by quantitative qPCR. We also quantified mRNA changes in IL13, IL10 and arginase I in WT and OC-STAMP deficient M2 macrophages.

Results: k/bxn-treated OC-STAMP deficient mice demonstrated extensive bone loss in the tibia (10 ± 0.9 Vs 22 ± 2, p = 0.0001), femur (12 ± 1 Vs 26 ± 2.5, p = 0.0001), talus (53 ± 2 Vs 58 ± 2, p = 0.0001), and increased pannus infiltration compared to WT mice. Surprisingly, the absence of DC-STAMP in OC-STAMP deficient mice treated with k/bxn sera was associated with decreased bone resorption in femur (16.3 ± 5, p = 0.05 ), tibia (15 ± 5, p =0.01) and ankle (51 ± 3.6, p = 0.02), compared to WT but bone loss was significantly lower than observed previously in DC-STAMP^-/- TNF-Tg mice. We assessed OC-STAMP expression by quantitative PCR in immune cells and found that OC-STAMP is expressed by spleen macrophages (51.9 ± 0.6, p ≤ 0.001), DCs (304 ± 24, p = 0.002), neutrophils (126 ± 13, p = 0.003), M2 macrophages (350 ± 17, p = 0.001 ), CD4 (1.8 ± 0.014) and CD8 T cells (7.9 ± 0.5, p = 0.0002). Its expression was low or absent in M1 macrophages (4.5 ± 0.01, p ≤ 0.0001) and CD115⁺ cells (1 ± 0.01, p ≤ 0.001), respectively. OC-STAMP deficient M2 macrophages showed impaired expression of IL13 (14.5 ± 1.6 Vs. 0.1 ± 0.005, p = 0.004 ), arginase I (55 ± 6.7, Vs. 1.3 ± 0.07, p = 0.006) and IL10 (0.056 ± 0.03, Vs 79 ± 1.9, p ≤ 0.001) compared with WT macrophages.

Conclusion: Ablation of OC-STAMP in the K/RxN arthritis model dramatically enhanced synovitis and bone loss in direct contrast to the findings observed with DC-STAMP knockout mice. OC-STAMP modulates synovial inflammation by inducing the expression of immunosuppressive cytokines and factors expressed by M2 macrophages. In the DC-STAMP/OC-STAMP knockout the arthritis phenotype is dominated by the absence of OC-STAMP.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/osteoclast-specific-transmembrane-protein-oc-stamp-regulates-osteoclastogenesis-and-inhibits-inflammation-in-an-acute-arthritis-model/