Netrin-1 Is a Critical Autocrine/Paracrine Factor for Osteoclast Differentiation

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  • Aránzazu Mediero
    Division of Translational MedicineDepartment of MedicineNYU School of MedicineNew YorkNYUSA
  • Bhama Ramkhelawon
    Leon H Charney Division of CardiologyDepartment of MedicineNYU School of MedicineNew YorkNYUSA
  • Miguel Perez-Aso
    Division of Translational MedicineDepartment of MedicineNYU School of MedicineNew YorkNYUSA
  • Kathryn J. Moore
    Leon H Charney Division of CardiologyDepartment of MedicineNYU School of MedicineNew YorkNYUSA
  • Bruce N. Cronstein
    Division of Translational MedicineDepartment of MedicineNYU School of MedicineNew YorkNYUSA

書誌事項

公開日
2014-12-08
権利情報
  • https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model
DOI
  • 10.1002/jbmr.2421
公開者
Oxford University Press (OUP)

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<jats:title>Abstract</jats:title> <jats:sec> <jats:title> </jats:title> <jats:p>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. © 2015 American Society for Bone and Mineral Research.</jats:p> </jats:sec>

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