Defective Entry into Mitosis 1 (Dim1) Negatively Regulates Osteoclastogenesis by Inhibiting the Expression of Nuclear Factor of Activated T-cells, Cytoplasmic, Calcineurin-dependent 1 (NFATc1)

Background: The potential role of Dim1 in RANKL-mediated induction of osteoclast differentiation is unknown. Results: Dim1 directly interacts with c-Fos to diminish the expression of NFATc1 target genes that are essential for RANKL-induced osteoclatogenesis. Conclusion: Dim1 functions as a negative regulator of RANKL-induced osteoclast differentiation. Significance: Understanding of the inhibitory role of Dim1 in RANKL-induced osteoclastogenesis might provide therapeutic benefits for treating various types of bone diseases. Bone remodeling is a continuous process of osteoblastic bone formation and osteoclastic bone resorption to maintain normal bone mass. NFATc1 is the master regulator of osteoclastogensis and transcriptionally activated by c-Fos and NF-B in response to receptor activator of NF-B ligand (RANKL) treatment. Defective entry into mitosis 1 (Dim1) is a nuclear protein that is implicated in pre-mRNA splicing and cell cycle progression, but the possible role of Dim1 in regulating other cellular processes remains unknown. Here, we demonstrate that Dim1 attenuates RANKL-induced osteoclastogenesis by targeting NFATc1 signaling pathway. Expression levels of Dim1 and NFATc1 are significantly increased during the formation of multinucleated osteoclasts. RNAi-mediated knockdown of Dim1 markedly enhances the expression of NFATc1 and its target genes, leading to the increase of RANKL-induced osteoclastogenesis in bone marrow-derived macrophages. Conversely, ectopic expression of Dim1 decreases RANKL-induced osteoclast differentiation by silencing NFATc1 and its target genes, further linking Dim1 to the dynamic regulation of osteoclastogenesis. Consistent with this notion, ChIP and interaction studies show that Dim1 directly associates with c-Fos and prevents c-Fos from binding to the NFATc1 promoter, resulting in targeted inactivation of the NFATc1 gene. Therefore, our studies reveal an unrecognized role for Dim1 as a master modulator of osteoclast differentiation, as well as the molecular mechanism underlying its repressive action toward osteoclastogensis.