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

• Published in: American journal of physiology: endocrinology and metabolism 2003-01, Vol.284 (1), p.E219-E227
• Main Authors: Chattopadhyay, Naibedya, MacLeod, R. J, Tfelt-Hansen, Jacob, Brown, Edward M
• Format: Article
• Language: English
• Subjects: Antibodies - pharmacology; Calcitriol - pharmacology; Cell Differentiation - drug effects; Cell Division - drug effects; Gene Expression; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - immunology; Hepatocyte Growth Factor - secretion; Humans; Kinetics; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Osteoblasts - pathology; Osteosarcoma - metabolism; Osteosarcoma - pathology; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Tumor Cells, Cultured
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00247.2002

Endocrine-Hypertension Division and Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 Several mesenchymally derived cells, including osteoblasts, secrete hepatocyte growth factor (HGF). 1 ,25(OH) 2 -vitamin D 3 [1,25(OH) 2 D 3 ] 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) 2 D 3 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) 2 D 3 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) 2 D 3 . 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) 2 D 3 on MG-63 cells can be accounted for by the concomitant 1,25(OH) 2 D 3 -induced inhibition of HGF production. osteoblast; proliferation; autocrine; mitogen-activated protein kinase; tyrosine kinase; hepatocyte growth factor