Abstract
Fibroblast growth factor-2 (FGF2) has been demonstrated to be a promising osteogenic factor for treating osteoporosis. Our earlier study shows that transplantation of mouse Sca-1+ hematopoietic stem/progenitor cells that are engineered to express a modified FGF2 leads to considerable endosteal/trabecular bone formation, but it also induces adverse effects like hypocalemia and osteomalacia. Here we report that the use of an erythroid specific promoter, β-globin, leads to a 5-fold decrease in the ratio of serum FGF2 to the FGF2 expression in the marrow cavity when compared to the use of a ubiquitous promoter spleen focus-forming virus (SFFV). The confined FGF2 expression promotes considerable trabeculae bone formation in endosteum and does not yield anemia and osteomalacia. The avoidance of anemia in the mice that received Sca1+ cells transduced with FGF2 driven by the β-globin promoter is likely due to attenuation of high-level serum FGF2-mediated stem cell mobilization observed in the SFFV-FGF2 animals. The prevention of osteomalacia is associated with substantially reduced serum Fgf23/hypophosphatemia, and less pronounced secondary hyperparathyroidism. Our improved stem cell gene therapy strategy represents one step closer to FGF2-based clinical therapy for systemic skeletal augmentation.
Highlights
Osteoporosis, or porous bones, is a disease that leads to an increased risk of fracture
Ter119+ cells in the spleen expressed fibroblast growth factor-2 (FGF2) at 20–50 fold lower levels compared to bone marrow (BM) Ter119+ cells and FGF2 was undetectable in mature red blood cells
We report that use of the b-globin promoter leads to a 5fold enrichment of FGF2 expression in the marrow compared to the ubiquitous promoter spleen focus-forming virus (SFFV)-mediated transgene expression
Summary
Osteoporosis, or porous bones, is a disease that leads to an increased risk of fracture. Current therapies and drugs in development range from bisphosphonates, parathyroid hormone (PTH), RANKL inhibitors or anti-sclerostin antibodies. These therapies cause significant side effects after long-term use [1,2,3]. After transplantation of mouse bone marrow (BM) Sca-1+ hematopoietic stem/progenitor cells that were transduced with a murine leukemia virus (MLV)-based vector expressing a modified FGF2 gene, we observed substantially enhanced trabecular bone formation at the endosteal surface [13]. The MLV-based HSC gene therapy yields FGF2 levels that are ,100-fold higher than physiological concentrations in serum, which may increase chances of unintended side-effects, including tumorigenesis. Mice with high-level serum FGF2 developed anemia and osteomalacia [13]
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