TY - JOUR

T1 - 1α,25(OH)2-vitamin D3 inhibits HGF synthesis and secretion from MG-63 human osteosarcoma cells

AU - Chattopadhyay, Naibedya

AU - MacLeod, R. J.

AU - Tfelt-Hansen, Jacob

AU - Brown, Edward M.

PY - 2003/1/1

Y1 - 2003/1/1

N2 - 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.

AB - 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.

KW - Autocrine

KW - Hepatocyte growth factor

KW - Mitogen-activated protein kinase

KW - Osteoblast

KW - Proliferation

KW - Tyrosine kinase

UR - http://www.scopus.com/inward/record.url?scp=0037230072&partnerID=8YFLogxK

M3 - Journal article

C2 - 12388161

AN - SCOPUS:0037230072

VL - 284

JO - A J P: Endocrinology and Metabolism (Online)

JF - A J P: Endocrinology and Metabolism (Online)

SN - 1522-1555

IS - 1 47-1

ER -