Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice.
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.
Mukherjee
Siddhartha
S
Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Raje
Noopur
N
Schoonmaker
Jesse A
JA
Liu
Julie C
JC
Hideshima
Teru
T
Wein
Marc N
MN
Jones
Dallas C
DC
Vallet
Sonia
S
Bouxsein
Mary L
ML
Pozzi
Samantha
S
Chhetri
Shweta
S
Seo
Y David
YD
Aronson
Joshua P
JP
Patel
Chirayu
C
Fulciniti
Mariateresa
M
Purton
Louise E
LE
Glimcher
Laurie H
LH
Lian
Jane B
JB
Stein
Gary
G
Anderson
Kenneth C
KC
Scadden
David T
DT
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*
D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib