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1α,25(OH)2-vitamin D3 inhibits HGF synthesis and secretion from MG-63 human osteosarcoma cells

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  • Naibedya Chattopadhyay
  • R. J. MacLeod
  • Tfelt, Jacob
  • Edward M. Brown

Several mesenchymally derived cells, including osteoblasts, secrete hepatocyte growth factor (HGF). 1α,25(OH)2-vitamin D3 [1,25(OH)2D3] inhibits proliferation and induces differentiation of MG-63 osteoblastic cells. Here we show that MG-63 cells secrete copious amounts of HGF and that 1,25(OH)2D3 inhibits HGF production. MG-63 cells also express HGF receptor (c-Met) mRNA, suggesting an autocrine action of HGF. Indeed, although exogenous HGF failed to stimulate cellular proliferation, neutralizing endogenous HGF with a neutralizing antibody inhibited MG-63 cell proliferation; moreover, inhibiting HGF synthesis with 1,25(OH)2D3 followed by addition of HGF rescued hormone-induced inhibition of proliferation. Nonneutralized cells displayed constitutive phosphorylation of c-Met and the mitogen-activated protein kinases mitogen/extracellular signal-regulated kinase (MEK) 1 and extracellular signal-regulated kinase (Erk) 1/2, which were inhibited by anti-HGF antibody. Constitutive phosphorylation of Erk1/2 was also abolished by 1,25(OH)2D3. Addition of HGF to MG-63 cells treated with neutralizing HGF antibody induced rapid phosphorylation of c-Met, MEK1, and Erk1/2. Thus endogenous HGF induces a constitutively active, autocrine mitogenic loop in MG-63 cells. The known antiproliferative effect of 1,25(OH)2D3 on MG-63 cells can be accounted for by the concomitant 1,25(OH)2D3-induced inhibition of HGF production.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Physiology - Endocrinology and Metabolism
Vol/bind284
Udgave nummer1 47-1
ISSN0193-1849
StatusUdgivet - 1 jan. 2003
Eksternt udgivetJa

ID: 203877963