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2014 ; 3
(ä): 543
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Functional heterogeneity of osteocytes in FGF23 production: the possible
involvement of DMP1 as a direct negative regulator
#MMPMID24991406
Lee JW
; Yamaguchi A
; Iimura T
Bonekey Rep
2014[]; 3
(ä): 543
PMID24991406
show ga
Fibroblast growth factor 23 (FGF23) and dentin matrix protein (DMP1) are
hallmarks of osteocytes in bone. However, the mechanisms underlying the actions
of DMP1 as a local factor regulating FGF23 and bone mineralization are not well
understood. We first observed spatially distinct distributions of FGF23- and
DMP1-positive osteocytic lacunae in rat femurs using immunohistochemistry.
Three-dimensional immunofluorescence morphometry further demonstrated that the
distribution and relative expression levels of these two proteins exhibited
reciprocally reversed patterns especially in midshaft cortical bone. These in
vivo findings suggest a direct role of DMP1 in FGF23 expression in osteocytes. We
next observed that the inoculation of recombinant DMP1 in UMR-106
osteoblast/osteocyte-like cells and long-cultured MC3T3-E1 osteoblastic cells
showed significant downregulation of FGF23 production. This effect was rescued by
incubation with an focal adhesion kinase (FAK) inhibitor or MEK
(mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase
(ERK)) inhibitor but not inhibitors of phosphoinositide 3-kinase or Rho kinase.
Consistently, the levels of phosphorylated FAK, ERK and p38 were significantly
elevated, indicating that exogenous DMP1 is capable of activating FAK-mediated
MAPK signaling. These findings suggest that DMP1 is a local, direct and negative
regulator of FGF23 production in osteocytes involved in the FAK-mediated MAPK
pathway, proposing a relevant pathway that coordinates the extracellular
environment of osteocytic lacunae and bone metabolism.