Absence of herpes virus entry mediator (HVEM) increases bone mass by attenuating receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis.

Abstract

Herpes virus entry mediator (HVEM), which is constitutively expressed at a high level on myeloid lineage cells, is also expressed on bone marrow-derived macrophages, suggesting that it may play a role in bone metabolism by affecting osteoclasts (OC) derived from bone marrow-derived macrophages. To address this question, we evaluated bone mass by micro-computed tomography and the number and activity of OC by tartrate-resistant acid phosphatase (TRAP) and pit formation on dentine slices, comparing HVEM-knockout mice with wild-type mice. The absence of HVEM led to a higher bone mass and to decreased levels of serum collagen type I fragments and serum TRACP5b in vivo. In vitro HVEM deficiency resulted in a reduced number and activity of OC and an impaired receptor activator of nuclear factor-κB ligand signaling through reduced activation of nuclear factor-κB and of nuclear factor of activated T-cells cytoplasmic 1. Exogenous soluble HVEM decreased expression of TRAP, whereas soluble LIGHT (a ligand of HVEM) increased it, indicating the occurrence of a positive signaling through HVEM during osteoclastogenesis. Our findings indicate that HVEM regulates bone remodeling via action on OC. The higher bone mass in the femurs of HVEM-knockout mice could be, at least in part, due to attenuated osteoclastogenesis and bone resorption resulting from decreased receptor activator of nuclear factor-κB ligand signaling in the OC.