title: Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK1 is associated with lytic bone disease.
abstract: Multiple myeloma (MM) lytic bone disease (LBD) is caused by osteoclast activation and osteoblast inhibition. RANK/RANKL/OPG play central roles in osteoclast activation and Wnt inhibitor DKK1 in osteoblast inhibition. The role of other Wnt inhibitors is less clear. We evaluated gene expression of osteoclast regulators (RANK, RANKL, OPG, TRAIL, MIP1A), Wnt inhibitors (DKK1, SFRP2, SFRP3, sclerostin, WIF1) and osteoblast transcription factors (RUNX2, osterix) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the bone marrow (BM) microenvironment using snap-frozen BM biopsies, thereby achieving minimal post-sampling manipulation, and gene expression profiling (GEP) data, reflecting the in vivo situation. We analyzed 110 biopsies from newly diagnosed patients with MM and monoclonal gammopathy of unknown significance (MGUS) and healthy volunteers. LBD was evaluated using standard radiographs and the bone resorption marker CTX-1. Protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Among Wnt inhibitors, only SFRP3 and DKK1 were significantly overexpressed in advanced LBD, correlating with protein levels. SFRP3 correlated with CTX-1. Our findings support osteoblast inhibition as the driving force behind MM LBD.
authors.affiliation: Department of Hematology.
authors.forename: Ida B
authors.initials: IB
authors.lastname: Kristensen
authors.forename: Jacob Haaber
authors.initials: JH
authors.lastname: Christensen
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lyng
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.forename: Lise
authors.initials: L
authors.lastname: Pedersen
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rasmussen
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.forename: Niels
authors.initials: N
authors.lastname: Abildgaard
mesh_terms: D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000473:pathology; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D009367:Neoplasm Staging; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010014:Osteolysis / Q000209:etiology; D059016:Tumor Microenvironment / Q000235:genetics*; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins; C501126:DKK1 protein, human