Novel extraneural role of neurite outgrowth inhibitor A: Modulation of osteoclastogenesis via positive feedback regulation of nuclear factor of activated T cell cytoplasmic 1

Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte lineage precursors upon receptor activator of NF-κB ligand (RANKL) stimulation. In a proteomic approach to identify proteins involved in osteoclastogenesis, we observed a dramatic increase in the expression of neurite outgrowth inhibitor A (Nogo-A) upon RANKL stimulation of mouse bone marrow macrophages (BMMs) in a nuclear factor of activated T cell cytoplasmic 1 (NFATc1)-dependent manner. The knockdown of Nogo-A in BMMs significantly reduced RANKL-dependent osteoclast differentiation accompanied by diminished NFATc1 induction, suggesting that a positive feedback mechanism is involved. Conversely, Nogo-A overexpression in BMMs as well as in RAW264.7 macrophages greatly augmented osteoclastogenesis, with concomitant increase in the NFATc1 induction. Both the mitogen-activated protein kinase (MAPK) pathway and calcium oscillation, which are central to RANKL-dependent NFATc1 activation and induction, were enhanced by Nogo-A. Finally, Nogo-A knockdown in mouse calvariae prevented interleukin 1 (IL-1)-induced bone loss. These findings not only reveal an unprecedented extraneural role of Nogo-A in osteoclastogenesis but also suggest a novel drug target against bone-lytic diseases.