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Blood, 1 April 2007, Vol. 109, No. 7, pp. 3024-3030.
Prepublished online as a Blood First Edition Paper on November 30, 2006; DOI 10.1182/blood-2006-07-034884.
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Submitted July 14, 2006
Accepted November 18, 2006
HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma
Therese Standal*, Niels Abildgaard, Unn-Merete Fagerli, Berit Stordal, Oyvind Hjertner, Magne Borset, and Anders Sundan
Dept of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Department of Haematology, Odense University Hospital, Odense, Denmark
Department of Immunology and Transfusion Medicine, St. Olav University Hospital, Trondheim, Norway
* Corresponding author; email: therese.standal{at}ntnu.no.
The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with - and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. HGF is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited BMP-induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSC) and the murin myoid cell line C2C12, as well as mineralization by human mesenchymal stem cells (hMSC). Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSC, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data was supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone specific alkaline phosphatase (rho=-0,45, p=0,008), in sera from 34 myeloma patients. These observations suggest that HGF inhibits bone formation in multiple myeloma.
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