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.