Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice
Siddhartha Mukherjee, … , Kenneth C. Anderson, David T. Scadden
Siddhartha Mukherjee, … , Kenneth C. Anderson, David T. Scadden
Published January 24, 2008
Citation Information: J Clin Invest. 2008;118(2):491-504. https://doi.org/10.1172/JCI33102.
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Research Article

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

Siddhartha Mukherjee, Noopur Raje, Jesse A. Schoonmaker, Julie C. Liu, Teru Hideshima, Marc N. Wein, Dallas C. Jones, Sonia Vallet, Mary L. Bouxsein, Samantha Pozzi, Shweta Chhetri, Y. David Seo, Joshua P. Aronson, Chirayu Patel, Mariateresa Fulciniti, Louise E. Purton, Laurie H. Glimcher, Jane B. Lian, Gary Stein, Kenneth C. Anderson, David T. Scadden

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Figure 1

Bzb treatment increases osteoblasts in vivo.

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Bzb treatment increases osteoblasts in vivo. (A) Mice treated with Bzb (...
(A) Mice treated with Bzb (0.3 mg/kg i.p.; 3 times/week) showed an increase in the levels of serum osteocalcin over 3 weeks compared with control-treated (saline-treated) mice. In contrast, serum osteocalcin decreased over time in control mice. P = 0.01 by Student’s t test; n = 5 mice each. (B) Micro-CT analysis revealed an increase in trabecular bone volume in drug-treated mice. A representative reconstruction of trabecular bone is shown as 3D reconstruction (left panel, mock treated; right panel, Bzb treated) and as cross sections (left panel, control; right panel, Bzb treated). Scale bar: 1.0 mm. (C) Colony formation from Bzb-treated versus saline-treated (mock-treated) animals showed increased CFU-F, increased Ops (CFU-Alk), and decreased adipocytic colonies (CFU-Adipo). *P = 0.007, n = 8 wells for CFU-F; †P < 0.01, n = 9 wells for CFU-Alk; ‡P = 0.01, n = 12 wells for CFU-Adipo. (D) Histomorphometric analysis of Bzb-treated animals showed increased trabecular connectivity, trabecular volume occupied by bone, and trabecular number. ΧP = 0.05, trabecular connectivity; ζP = 0.02, trabecular bone volume; #P = 0.03, trabecular number/mm. n = 4 femurs. (E) Histological sections of treated animals showed increased bone with normal architecture in trabeculae (H&E-stained samples) but with increased bone volume. Original magnification, ×40. (F) Increased osteoblast number per BSpm in distal femur was observed in Bzb-treated animals. **P = 0.02; n = 3. (G) Increase in mineralization rate in animals treated with Bzb. ††P < 0.01; n = 6. (H) No significant change was observed in TRAP-stained osteoclasts, quantified by osteoclasts/μm of BSpm. P = 0.53 by Student’s t test.