TREM-1, a negative regulator of human osteoclastogenesis

Abstract

Triggering receptor expressed on myeloid cells (TREMs) are a family of cell surface receptors that play important roles in innate and adaptive immunity. Among them, TREM-2 has been extensively studied for its role in osteoclast differentiation and its essential role in human osteoclastogenesis has been well established. However, much less has been discovered about the role of TREM-1 in human osteoclast differentiation. In this study, we investigate the role of TREM-1 in human osteoclast differentiation. Consistent with previous reports, TREM-2 expression was strongly increased during the generation of human osteoclast precursors. In contrast, TREM-1 expression was decreased during the generation of human osteoclast precursors. Stimulation of TREM-1 using agonistic anti-TREM-1 antibody resulted in suppression of RANKL-induced osteoclastogenesis, as evidenced by diminished formation of TRAP+ multinucleated cells. In addition, TREM-1 stimulation strongly suppressed RANKL-induced expression of osteoclast-related genes such as cathepsin K and NFATc1. TREM-1 stimulation also down-regulated gene expression and cell surface expression of M-CSF receptor that is essential for osteoclast differentiation and survival. In synovial fluid macrophages of rheumatoid arthritis (RA) patients, TREM-1 stimulation suppressed osteoclastogenesis. In conclusion, we demonstrate that TREM-1 acts as a negative regulator of human osteoclast differentiation and identify a novel mechanism of negative regulation of osteoclastogenesis that plays a role in inflammation.