Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.
Multiple myeloma (MM) develops devastating bone destruction with enhanced bone resorption and suppressed bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because a canonical Wingless-type (Wnt) signaling pathway has recently been shown to play an important role in osteoblast differentiation, we examined whether MM cells affect a canonical Wnt pathway to suppress bone formation. Conditioned media from RPMI8226 and U266 MM cell lines and primary MM cells suppressed in vitro mineralization as well as alkaline phosphatase activity in osteoblasts induced by bone morphogenetic protein 2 (BMP-2). These cell lines constitutively produced a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced bone destructive lesions also expressed sFRP-2. Furthermore, exogenous sFRP-2 suppressed osteoblast differentiation induced by BMP-2, and immunodepletion of sFRP-2 significantly restored mineralized nodule formation in vitro, suggesting a predominant role for MM cell-derived sFRP-2 in the impairment of bone formation by MM. Thus, in addition to enhanced osteolysis, MM cells also suppress bone formation at least in part through an inhibition of the canonical Wnt pathway by secreting sFRP-2.
Oshima
Takashi
T
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Abe
Masahiro
M
Asano
Jin
J
Hara
Tomoko
T
Kitazoe
Kenichi
K
Sekimoto
Etsuko
E
Tanaka
Yoichi
Y
Shibata
Hironobu
H
Hashimoto
Toshihiro
T
Ozaki
Shuji
S
Kido
Shinsuke
S
Inoue
Daisuke
D
Matsumoto
Toshio
T
D000818:Animals; D000906:Antibodies / Q000276:immunology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D000906:Antibodies; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins