Digoxin Attenuates Receptor Activation of NF-κB Ligand-Induced Osteoclastogenesis in Macrophages.

Background: Even though hypoxia-inducible factor-1 alpha (HIF-1 alpha) is among the transcriptional factors demonstrated to contribute to the formation of abdominal aortic aneurysms (AAAs), the precise mechanism has been unclear. Digoxin is known as an inhibitor of HIF-1 alpha, and shows a protective effect against the progression of AAAs. Objectives: We tested the effect of digoxin on osteoclastogenesis (OCG) and examined the pathway through which digoxin exerts inhibition of HIF-1 alpha. Materials and Methods: RAW 264.7 macrophage cells were cultured and stimulated by soluble receptor activator of NF-kappa B ligand (sRANKL) with or without digoxin. First, we tested the effect of digoxin to attenuate macrophage activation, which led to OCG, characterized by tartrate-resistant acid phosphatase (TRAP)-positive macrophages (TPMs). Results: The activation of TPMs stimulated by sRANKL was attenuated by digoxin treatment. Furthermore, the receptor activator of NF-kappa B (RANK)/receptor activator of NF-kappa B ligand (RANKL) complex signaling pathway, which is stimulated by HIF-1 alpha, was downregulated by digoxin treatment. Conclusions: These results show that digoxin attenuates OCG. By inhibition of HIF-1 alpha, digoxin decreases OCG through the downregulation of the RANK/RANKL signaling pathway. Therefore, digoxin is a potential candidate for medical treatment of AAAs.