title: Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation.
abstract: Bone metabolism is a vital process that involves resorption by osteoclasts and formation by osteoblasts, which is closely regulated by immune cells. The neuronal guidance protein Netrin-1 regulates immune cell migration and inflammatory reactions, but its role in bone metabolism is unknown. During osteoclast differentiation, osteoclast precursors increase expression of Netrin-1 and its receptor Unc5b. Netrin-1 binds, in an autocrine and paracrine manner, to Unc5b to promote osteoclast differentiation in vitro, and absence of Netrin-1 or antibody-mediated blockade of Netrin-1 or Unc5b prevents osteoclast differentiation of both murine and human precursors. We confirmed the functional relationship of Netrin-1 in osteoclast differentiation in vivo using Netrin-1-deficient (Ntn1(-/-) ) or wild-type (WT) bone marrow transplanted mice. Notably, Ntn1(-/-) chimeras have markedly diminished osteoclasts, as well as increased cortical and trabecular bone density and volume compared with WT mice. Mechanistic studies revealed that Netrin-1 regulates osteoclast differentiation by altering cytoskeletal assembly. Netrin-1 increases regulator of Rho-GEF subfamily (LARG) and repulsive guidance molecule (RGMa) association with Unc5b, which increases expression and activation of cytoskeletal regulators RhoA and focal adhesion kinase (FAK). Netrin-1 and its receptor Unc5b likely play a role in fusion of osteoclast precursors because Netrin-1 and DC-STAMP are tightly linked. These results identify Netrin-1 as a key regulator of osteoclast differentiation that may be a new target for bone therapies.
authors.affiliation: Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, NY, USA.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Mediero
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez-Aso
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology*; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D011956:Receptors, Cell Surface / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C577223:Arhgef12 protein, mouse; C499636:DC-STAMP protein, mouse; D008565:Membrane Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; C091279:neogenin; D000075388:Netrin-1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein
keywords: FAK; NETRIN-1; OSTEOCLAST DIFFERENTIATION; RHOA; UNC5B