Original Full Length ArticleSialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone loss, but not joint destruction, in murine antigen-induced arthritis

- We examined the role of Siglec-15 in joint destruction and peri-articular bone loss in a mouse model of AIA.
- Development of arthritis and joint destruction in Siglec-15−/− mice was equal to that in WT mice.
- Siglec-15−/− mice are protected from periarticular bone loss in AIA.
- Siglec-15 plays an important role in osteoclastogenesis under inflammatory conditions.
- Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction in inflammatory arthritis.

Osteoclastogenesis requires immunoreceptor tyrosine-based activation motif signaling. Multiple immunoreceptors associated with immunoreceptor tyrosine-based activation motif adaptor proteins, including DNAX-activating protein 12 kDa (DAP12) and Fc receptor common γ (FcRγ), have been identified in osteoclast lineage cells, and some are involved in arthritis-induced bone destruction. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with DAP12. Whether Siglec-15 is involved in arthritis-induced bone lesions, however, remains unknown. Here we used a murine antigen-induced arthritis model to examine the role of Siglec-15 in the development of bone lesions induced by joint inflammation. Arthritis was unilaterally induced in the knee joints of 8-week-old female wild-type (WT) and Siglec-15−/− mice, and the contralateral knees were used as a control. The degree of joint inflammation, and cartilage and subchondral bone destruction in Siglec-15−/− mice was comparable to that in WT mice, indicating that Siglec-15 is not involved in the development of arthritis and concomitant cartilage and subchondral bone destruction. On the other hand, the degree of periarticular bone loss in the proximal tibia of the arthritic knee was significantly lower in Siglec-15−/− mice compared to WT mice. Although osteoclast formation in the metaphysis was enhanced in both WT and Siglec-15−/− mice after arthritis induction, mature multinucleated osteoclast formation was impaired in Siglec-15−/− mice, indicating impaired osteoclast bone resorptive function in the periarticular regions of the arthritic joint in Siglec-15−/− mice. Confirming this result, Siglec-15−/− primary unfractionated bone marrow cells harvested from arthritic femurs and tibiae failed to develop into mature multinuclear osteoclasts. Our findings suggest that Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction, in inflammatory arthritis, such as rheumatoid arthritis.