TGF-Î² Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growth
MetadataShow full item record
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-Î², 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-Î² and its inhibition in bone formation and tumor growth in MM.
Methodology/Principal Findings: TGF-Î² 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-Î². Inhibitors for a TGF-Î² type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-Î² inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-Î² 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-Î² 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-Î² 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-Î² appears to be an important therapeutic target in MM bone lesions.
CitationPLoS One. 2010 Mar 25; 5(3):e9870
- TGF-β-related mechanisms of bone destruction in multiple myeloma.
- Authors: Matsumoto T, Abe M
- Issue date: 2011 Jan
- Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis.
- Authors: Karsdal MA, Larsen L, Engsig MT, Lou H, Ferreras M, Lochter A, Delaissé JM, Foged NT
- Issue date: 2002 Nov 15
- [Mechanisms for formation of myeloma bone disease].
- Authors: Yata K, Abe M, Matsumoto T
- Issue date: 2008 Apr
- The p55 TNF receptor mediates TNF inhibition of osteoblast differentiation independently of apoptosis.
- Authors: Gilbert LC, Rubin J, Nanes MS
- Issue date: 2005 May
- Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2.
- Authors: Sowa H, Kaji H, Hendy GN, Canaff L, Komori T, Sugimoto T, Chihara K
- Issue date: 2004 Sep 24