title: Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells -Implications for myeloma bone disease.
abstract: Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA-6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Julia
authors: J
authors: Dotterweich
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Katrin
authors: K
authors: Schlegelmilch
authors: DNA-Analytics Core Facility, Biocenter and Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany.
authors: Alexander
authors: A
authors: Keller
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Beate
authors: B
authors: Geyer
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Doris
authors: D
authors: Schneider
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Sabine
authors: S
authors: Zeck
authors: Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors: Robert J J
authors: RJ
authors: Tower
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Regina
authors: R
authors: Ebert
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany. Electronic address: f-jakob.klh@uni-wuerzburg.de.
authors: Franz
authors: F
authors: Jakob
authors: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
authors: Norbert
authors: N
authors: Schütze
mesh_terms: D000368:Aged; D000075803:Angiopoietin-Like Protein 4 / Q000235:genetics / Q000378:metabolism; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D001847:Bone Diseases / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology*; D002448:Cell Adhesion; D002450:Cell Communication; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology*; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D015203:Reproducibility of Results; D059467:Transcriptome / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D018941:Antigens, CD19
keywords: Angiopoietin-like 4; Bone disease; Gene expression profiling; Mesenchymal stem cells; Multiple myeloma; Osteogenic precursor cells