title: Novel extraneural role of neurite outgrowth inhibitor A: modulation of osteoclastogenesis via positive feedback regulation of nuclear factor of activated T cell cytoplasmic 1.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Cheol Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Woo-Shin
authors.initials: WS
authors.lastname: Kim
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009185:Myelin Proteins / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D000070798:Nogo Proteins; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D009185:Myelin Proteins; D050778:NFATC Transcription Factors; D000070798:Nogo Proteins; D053245:RANK Ligand; C000603199:RTN4 protein, human; D011994:Recombinant Proteins; C000603201:Rtn4 protein, mouse