title: Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth.
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-beta, 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-beta and its inhibition in bone formation and tumor growth in MM.
  
  
  RESULTS
  TGF-beta 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-beta. Inhibitors for a TGF-beta type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-beta inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-beta 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-beta inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models.
  
  
  CONCLUSIONS
  The present study demonstrates that TGF-beta 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-beta appears to be an important therapeutic target in MM bone lesions.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kido
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.forename: Osamu
authors.initials: O
authors.lastname: Tanaka
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yata
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003907:Dexamethasone / Q000494:pharmacology; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology*; D011817:Rabbits; D019947:Receptors, Interleukin-6 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D008558:Melphalan