title: Production of Wnt inhibitors by myeloma cells: potential effects on canonical Wnt pathway in the bone microenvironment.
abstract: Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.
authors: Hematology and Bone Marrow Transplantation Center, Department of Internal Medicine and Biomedical Science, University of Parma, Parma, Italy. N_giuliani@yahoo.com
authors: Nicola
authors: N
authors: Giuliani
authors: Francesca
authors: F
authors: Morandi
authors: Sara
authors: S
authors: Tagliaferri
authors: Mirca
authors: M
authors: Lazzaretti
authors: Gaetano
authors: G
authors: Donofrio
authors: Sabrina
authors: S
authors: Bonomini
authors: Roberto
authors: R
authors: Sala
authors: Marcellina
authors: M
authors: Mangoni
authors: Vittorio
authors: V
authors: Rizzoli
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins; C501126:DKK1 protein, human