Bone-protective Functions of Netrin 1 Protein

Kenta Maruyama,Takahiko Kawasaki,Masahide Hamaguchi,Motomu Hashimoto,Moritoshi Furu,Hiromu Ito,Takao Fujii,Naoki Takemura,Thangaraj Karuppuchamy,Takeshi Kondo,Takumi Kawasaki,Masahiro Fukasaka,Takuma Misawa,Tatsuya Saitoh,Yutaka Suzuki,Mikaël M Martino,Yutaro Kumagai,Shizuo Akira

doi:10.1074/jbc.m116.738518

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.

Highlights

Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration
Netrin 1 Is Expressed in Osteoblasts and Synovial Fibroblasts—To identify the netrin 1-producing cell population in the osteoimmune system, we examined netrin 1 expression in various hematopoietic and mesenchymal cell types
We found that netrin 1 is highly expressed in osteoblasts and synovial fibroblasts

Summary

Edited by Amanda Fosang

Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. RA is characterized by proliferating synovial fibroblasts, severe joint inflammation, and bone erosion, accompanied by hyperactivated bone-degrading osteoclasts [1], large multinucleate cells that differentiate from the macrophage lineage [2]. Both osteoblasts and synovial fibroblasts express the RANK ligand (RANKL) and M-CSF. Netrin 1 is an axon guidance cue that mediates the attraction and repulsion of neural axons by regulating cytoskeletal rearrangements (16 –19) The determinant of these variable functions is the expression of netrin 1 surface receptor UNC5b on neural cells. These observations prompted us to explore whether netrin 1 regulates osteoclast multinucleation

Results

Discussion

Experimental Procedures