Compositions and methods for osteogenic gene therapy

A method of identifying an agent that modulates bone growth, maintenance and repair, the method comprising:

• harvesting at least one hematopoietic stem cell;
• transducing and expressing in the at least one mouse hematopoietic stem cell at least one heterologous nucleic acid comprising a polynucleotide sequence that encodes an osteogenic growth factor comprising a secretable analog of human fibroblast growth factor-2 (FGF-2) encoded by a nucleic acid sequence comprising in a 5′ to 3′ direction:
• a polynucleotide sequence that encodes a bone morphogenetic protein 2/4 (BMP2/4) hybrid secretion signal peptide sequence and a polynucleotide sequence that encodes a mature human FGF-2 polypeptide comprising a mutation that results in the substitution of an alanine for a cysteine in amino acid position 70 of FGF-2 and a mutation that results in the substitution of an asparagine for a cysteine in amino acid position 88 of FGF-2;
• introducing the at least one hematopoietic stem cell or a progeny thereof into an immunologically compatible mouse, wherein expression of the secretable analog of human FGF-2 produces an increase in serum level of FGF-2 as compared to immunologically compatible mice engrafted with hematopoietic stem cells transduced with the BMP2/4 hybrid secretion signal peptide sequence and a wild type FGF-2-control;
• administering an agent to the mouse;
• and
• screening for modulation of FGF-2 secretion, wherein an increase in FGF-2 secretion identifies an agent that increases bone growth.