Regulatory Mechanism of RANK Gene Expression during Osteoclastic Differentiation of Bone Marrow Macrophage/Monocyte Lineage

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Receptor activator of NF-kappaB(RANK) expressed on osteoclasts and their precursors is a receptor for RANK Ligand(RANKL). RANKL-RANK interaction induces genes essential for the differentiation of osteoclasts through the binding of NFATc1 to target gene promoters. We have cloned a 6-kb fragment containing the 5'-flanking region of the mouse RANK gene and have analyzed the binding elements such as PU. 1(-480), and MITF(-100). Here, we showed the regulatory mechanism of RANK gene transcription through the NFAT(-370) and CRE/AP-1 binding sites(-240). Furthermore, we have identified a novel alternative splicing variant of mouse RANK gene that contains a new intervening exon between exon 1 and exon 2 of mouse full-length RANK mRNA, and shown that variant RANK is a novel osteoclast suppressor that reduces the number of RANKL-induced mature osteoclasts mainly by negating the anti-apoptotic effect of RANKL.