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.PDGFB | hematopoietic stem cells | bone formation | gene therapy

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During limb development, fibroblast growth factors (FGFs) from the apical ectodermal ridge (AER) regulate the expression of Sonic hedgehog (SHH) in the underlying posterior distal mesoderm. The molecules or pathways involved in the regulation of SHH by FGF are unknown. A recent study suggests that ETS and ETV, members of the ETS transcription factor family, are intermediate regulators in the Fgf to Shh cascade and directly interact with the limb‐specific Shh regulatory region in the murine limb model. To determine whether this was a conserved function of ETS/ETV transcription factors, we used the chick model and examined ETS2/ETV5 expression by in situ hybridization following ectopic application of FGF in the posterior limb bud, an assay known to induce SHH. ETV5 is expressed in the distal mesoderm sub‐adjacent to the AER and overlaps the SHH expression domain. ETS2 expression is most prominent in the developing chick zeugopod and appears to correlate with the condensing radius and ulna. The posterior expression of ETS2 is more robust than its anterior expression. Both factors show increased expression around ectopically applied FGF2‐laden beads at 24 hours after bead implantation. These data demonstrate expression patterns that spatially complement and overlap the SHH expression domain. Furthermore, both factors are upregulated by ectopic FGF prior to or coincident with SHH upregulation. These data support a role for ETS transcription factors in the regulation of SHH by FGF.