Molecular structure, expression, and the emerging role of Siglec-15 in skeletal biology and cancer

Siglec‐15, a Siglec family member and type‐1 transmembrane protein, is expressed mainly in human macrophages and dendritic cells. It is comprised of a lysine‐containing transmembrane domain, two extracellular immunoglobulin (Ig)‐like domains and a short cytoplasmic domain. Siglec‐15 is highly conserved in vertebrates and acts as an immunoreceptor. It exerts diverse functions on osteoclast physiology as well as the tumor microenvironment. Siglec‐15 interacts with adapter protein DAP12 ‐ Syk signaling pathway to regulate the RANKL/RANK‐mediatedPI3K, AKT, and ERK signaling pathways during osteoclast formation in vitro. Consistently, the lack of the Siglec‐15 gene in mice leads to impaired osteoclast activity and osteopetrosis in vivo. In addition, Siglec‐15 is expressed by tumor‐associated macrophages (TAMs) and regulates the tumor microenvironment by activating the SYK/MAPK signaling pathway. Interestingly, Siglec‐15 shares sequence homology to programmed death‐ligand 1 (PD‐L1) and has a potential immune‐regulatory role in cancer immunology. Thus, Siglec‐15 might also represent an alternative target for the treatment of cancers that do not respond to anti‐PD‐L1/PD‐1 immunotherapy. Understanding the role of Siglec‐15 in osteoclasto genesis and the tumor microenvironment will help us to develop new treatments for bone disorders and cancer.