Bone-protective Functions of Netrin 1 Protein

J Biol Chem. 2016 Nov 11;291(46):23854-23868. doi: 10.1074/jbc.M116.738518. Epub 2016 Sep 28.

Abstract

Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.

Keywords: arthritis; cell fusion; interleukin 17A (IL-17 or IL-17A); netrin 1; osteoblast; osteoclast; osteoporosis; rheumatoid arthritis.

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Bone Resorption / genetics
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control*
  • Disease Models, Animal
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Mutant Strains
  • Nerve Growth Factors / biosynthesis
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / pharmacology*
  • Netrin Receptors
  • Netrin-1
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Proto-Oncogene Proteins c-vav / genetics
  • Proto-Oncogene Proteins c-vav / metabolism
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / pharmacology*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Neuropeptides
  • Ntn1 protein, mouse
  • Proto-Oncogene Proteins c-vav
  • Rac1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Vav3 protein, mouse
  • Netrin-1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • rac1 GTP-Binding Protein