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2016 ; 291
(46
): 23854-23868
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Bone-protective Functions of Netrin 1 Protein
#MMPMID27681594
Maruyama K
; Kawasaki T
; Hamaguchi M
; Hashimoto M
; Furu M
; Ito H
; Fujii T
; Takemura N
; Karuppuchamy T
; Kondo T
; Kawasaki T
; Fukasaka M
; Misawa T
; Saitoh T
; Suzuki Y
; Martino MM
; Kumagai Y
; Akira S
J Biol Chem
2016[Nov]; 291
(46
): 23854-23868
PMID27681594
show ga
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.
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