title: Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease.
abstract: Lytic bone disease (LBD) in multiple myeloma (MM) is caused by osteoclast hyperactivation and osteoblast inhibition. Based on in vitro studies, the hepatocyte growth factor (HGF) pathway is thought to be central in osteoblast inhibition. We evaluated the gene expression of the HGF pathway in vivo using bone marrow biopsies (BMBs) of patients with MM and monoclonal gammopathy of undetermined significance (MGUS), and healthy volunteers (HV). BMBs (N = 110) obtained at diagnosis were snap-frozen and used to evaluate gene expression by quantitative reverse transcription polymerase chain reaction. LBD was evaluated using standard radiographs. Enzyme-linked immunosorbent assay (ELISA) was performed on matched bone marrow plasma and immunohistochemistry on matched formalin-fixed paraffin-embedded biopsies. Gene expression of HGF, SDC1, and MET in BMBs were significantly altered in MM versus HV and MGUS, and HGF and MET correlated with the extent of LBD. A significant correlation between gene and protein expression levels was observed for SDC1 (Syndecan-1) and HGF. The HGF bone marrow plasma level was significantly lower in MM patients with no/limited versus advanced LBD. Our novel approach using snap-frozen BMBs seems generally applicable because it allows evaluation of gene expression independent of the extent of MM plasma-cell infiltration. Our study highlights the importance of the HGF pathway in MM LBD.
authors: Department of Haematology, Odense University Hospital, Odense, Denmark. ibkristensen@health.sdu.dk
authors: Ida B
authors: IB
authors: Kristensen
authors: Jacob H
authors: JH
authors: Christensen
authors: Maria B
authors: MB
authors: Lyng
authors: Michael B
authors: MB
authors: Møller
authors: Lise
authors: L
authors: Pedersen
authors: Lars M
authors: LM
authors: Rasmussen
authors: Henrik J
authors: HJ
authors: Ditzel
authors: Niels
authors: N
authors: Abildgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism*; D058575:Decorin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010014:Osteolysis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D053668:Syndecan-1 / Q000096:biosynthesis* / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: C546878:DCN protein, human; D058575:Decorin; C066855:HGF protein, human; D009363:Neoplasm Proteins; D020033:Protein Isoforms; C508241:SDC1 protein, human; D053668:Syndecan-1; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met