TGF-β Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growth

Hdl Handle:
http://hdl.handle.net/10675.2/580
Title:
TGF-β Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growth
Authors:
Takeuchi, Kyoko; Abe, Masahiro; Hiasa, Masahiro; Oda, Asuka; Amou, Hiroe; Kido, Shinsuke; Harada, Takeshi; Tanaka, Osamu; Miki, Hirokazu; Nakamura, Shingen; Nakano, Ayako; Kagawa, Kumiko; Yata, Kenichiro; Ozaki, Shuji; Matsumoto, Toshio
Abstract:
; Background: Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-β, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-β and its inhibition in bone formation and tumor growth in MM.; Methodology/Principal Findings: TGF-β suppressed OB differentiation from bone marrow stromal cells and MC3T3-E1 preosteoblastic cells, and also inhibited adipogenesis from C3H10T1/2 immature mesenchymal cells, suggesting differentiation arrest by TGF-β. Inhibitors for a TGF-β type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-β inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-β inhibition expedited OB differentiation in parallel with suppression of MM cell growth. The anti-MM activity was elaborated exclusively by terminally differentiated OBs, which potentiated the cytotoxic effects of melphalan and dexamethasone on MM cells. Furthermore, TGF-β inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models.; Conclusions/Significance: The present study demonstrates that TGF-β inhibition releases stromal cells from their differentiation arrest by MM and facilitates the formation of terminally differentiated OBs, and that terminally differentiated OBs inhibit MM cell growth and survival and enhance the susceptibility of MM cells to anti-MM agents to overcome the drug resistance mediated by stromal cells. Therefore, TGF-β appears to be an important therapeutic target in MM bone lesions.
Citation:
PLoS One. 2010 Mar 25; 5(3):e9870
Issue Date:
25-Mar-2010
URI:
http://hdl.handle.net/10675.2/580
DOI:
10.1371/journal.pone.0009870
PubMed ID:
20360846
PubMed Central ID:
PMC2845613
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorTakeuchi, Kyokoen_US
dc.contributor.authorAbe, Masahiroen_US
dc.contributor.authorHiasa, Masahiroen_US
dc.contributor.authorOda, Asukaen_US
dc.contributor.authorAmou, Hiroeen_US
dc.contributor.authorKido, Shinsukeen_US
dc.contributor.authorHarada, Takeshien_US
dc.contributor.authorTanaka, Osamuen_US
dc.contributor.authorMiki, Hirokazuen_US
dc.contributor.authorNakamura, Shingenen_US
dc.contributor.authorNakano, Ayakoen_US
dc.contributor.authorKagawa, Kumikoen_US
dc.contributor.authorYata, Kenichiroen_US
dc.contributor.authorOzaki, Shujien_US
dc.contributor.authorMatsumoto, Toshioen_US
dc.date.accessioned2012-10-26T16:26:47Z-
dc.date.available2012-10-26T16:26:47Z-
dc.date.issued2010-03-25en_US
dc.identifier.citationPLoS One. 2010 Mar 25; 5(3):e9870en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20360846en_US
dc.identifier.doi10.1371/journal.pone.0009870en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/580-
dc.description.abstractBackground: Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-β, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-β and its inhibition in bone formation and tumor growth in MM.en_US
dc.description.abstractMethodology/Principal Findings: TGF-β suppressed OB differentiation from bone marrow stromal cells and MC3T3-E1 preosteoblastic cells, and also inhibited adipogenesis from C3H10T1/2 immature mesenchymal cells, suggesting differentiation arrest by TGF-β. Inhibitors for a TGF-β type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-β inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-β inhibition expedited OB differentiation in parallel with suppression of MM cell growth. The anti-MM activity was elaborated exclusively by terminally differentiated OBs, which potentiated the cytotoxic effects of melphalan and dexamethasone on MM cells. Furthermore, TGF-β inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models.en_US
dc.description.abstractConclusions/Significance: The present study demonstrates that TGF-β inhibition releases stromal cells from their differentiation arrest by MM and facilitates the formation of terminally differentiated OBs, and that terminally differentiated OBs inhibit MM cell growth and survival and enhance the susceptibility of MM cells to anti-MM agents to overcome the drug resistance mediated by stromal cells. Therefore, TGF-β appears to be an important therapeutic target in MM bone lesions.en_US
dc.rightsTakeuchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectDiabetes and Endocrinology/Bone and Mineral Metabolismen_US
dc.subjectHematology/Myelomaen_US
dc.subjectOncology/Myelomas and Lymphoproliferative Diseasesen_US
dc.titleTGF-β Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growthen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2845613en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-
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