PDGFB-based stem cell gene therapy increases bone strength in the mouse
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Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved June 5, 2015 (received for review January 27, 2015)

Significance
Osteoporosis is a morbid disease afflicting millions of people worldwide. To unlock the unique regenerative powers of the skeleton that have not yet been exploited, we used stem cell gene therapy to dramatically increase bone formation at sites where bone is lost during osteoporosis. Our therapy tremendously increased de novo trabecular bone formation and trabecular connections, resulting in a large increase in bone strength. Our therapy has clinical potential, may serve as a prototype for future skeletal stem cell gene therapies, and is a model for mechanistic studies of de novo trabecular bone formation.
Abstract
Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1+ cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB–transduced Sca1+ cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.
Footnotes
- ↵1To whom correspondence should be addressed. Email: xzhang{at}llu.edu.
Author contributions: D.J.B., K.-H.W.L., and X.-B.Z. designed research; W.C., J.B.-J., A.N., J.B.K., and C.H.R. performed research; J.B.-J. contributed new reagents/analytic tools; W.C., C.H.R., and X.-B.Z. analyzed data; and W.C., D.J.B., K.-H.W.L., and X.-B.Z. wrote the paper.
Conflict of interest statement: A provisional patent application has been filed on the basis of some of the findings. D.J.B., K.-H.W.L., X.-B.Z., and W.C. are the coinventors.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1501759112/-/DCSupplemental.
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