Abstract
Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγnull (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism.
Highlights
Environmental factors, including infectious agents, contribute to the pathogenesis of autoimmune diseases along with genetic factors
We have previously reported that Epstein-Barr virus (EBV) infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/ Shi-scid/IL-2Rγnull mice; the underlying mechanisms are not known
We have previously reported that EBV-infected humanized NOG (hu-NOG) mice develop erosive arthritis with histological features of rheumatoid arthritis (RA), such as massive synovial proliferation, bone erosion, and bone marrow edema [25]
Summary
Environmental factors, including infectious agents, contribute to the pathogenesis of autoimmune diseases along with genetic factors. The Epstein-Barr virus (EBV), a human herpesvirus infecting > 90% of the global adult population, is associated with infectious mononucleosis, lymphoproliferative disorders of immunocompromised hosts, Burkitt’s lymphoma, and nasopharyngeal carcinoma. EBV is suggested to be associated with autoimmune diseases, such as rheumatoid arthritis (RA) [1,2,3,4,5,6,7,8,9], Sjogren’s syndrome [2,10,11,12], systemic lupus erythematosus [13,14,15], autoimmune thyroid disorders [16,17], and multiple sclerosis [18,19]. EBV-infected plasma cells producing antibodies to citrullinated peptides were recently detected in the synovial lymphoid structures of RA [21]
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