IL1ß and TNFα promote RANKL-dependent adseverin expression and osteoclastogenesis.

Adseverin is an actin-binding protein involved in osteoclastogenesis, but its role in inflammation-induced bone loss is not well-defined. Here, we examined whether IL1ß and TNFα regulate adseverin expression to control osteoclastogenesis in mouse primary monocytes and RAW264.7 cells. Adseverin was colocalized with subcortical actin filaments and was enriched in the fusopods of fusing cells. In precursor cells, adseverin overexpression boosted the formation of RANKL-induced multinucleated cells. Both IL1ß and TNFα enhanced RANKL-dependent TRAcP activity by 1.6-fold and multinucleated cell formation (cells with ≥3 nuclei) by 2.6- and 3.3-fold, respectively. However, IL1ß and TNFα did not enhance osteoclast formation in adseverin-knockdown cells. RANKL-dependent adseverin expression in bone marrow cells was increased by both IL1ß (5.4-fold) and TNFα (3.3-fold). Luciferase assays demonstrated that this expression involved transcriptional regulation of the adseverin promoter. Activation of the promoter was restricted to a 1118 bp sequence containing an NF-κB binding site, upstream of the transcription start site. TNFα also promoted RANKL-induced osteoclast precursor cell migration. We conclude that IL1ß and TNFα enhance RANKL-dependent expression of adseverin, which contributes to fusion processes in osteoclastogenesis.