title: Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice.
abstract: Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Schoonmaker
authors.forename: Julie C
authors.initials: JC
authors.lastname: Liu
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Marc N
authors.initials: MN
authors.lastname: Wein
authors.forename: Dallas C
authors.initials: DC
authors.lastname: Jones
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.forename: Shweta
authors.initials: S
authors.lastname: Chhetri
authors.forename: Y David
authors.initials: YD
authors.lastname: Seo
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Aronson
authors.forename: Chirayu
authors.initials: C
authors.lastname: Patel
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Gary
authors.initials: G
authors.lastname: Stein
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation; D005260:Female; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib