Gene Therapy for Bone Regeneration

Abstract

Efficacious bone regeneration could revolutionize the clinical management of many bone and musculoskeletal disorders. Bone has the unique ability to regenerate and continuously remodel itself throughout life. However, clinical situations arise when bone is unable to heal itself, as with segmental bone loss, fracture non-union, and failed spinal fusion. This leads to significant morbidity and mortality. Current attempts at improved bone healing have been met with limited success, fueling the development of improved techniques. Gene therapy in many ways represents an ideal approach for augmenting bone regeneration. Gene therapy allows specific gene products to be delivered to a precise anatomic location. In addition, the level of transgene expression as well as the duration of expression can be regulated with current techniques. For bone regeneration, the gene of interest should be delivered to the fracture site, expressed at appropriate levels, and then deactivated once the fracture has healed. Delivery of biological factors, mostly bone morphogenetic proteins (BMPs), has yielded promising results both in animal and clinical studies. There has also been tremendous work on discovering new growth factors and exploring previously defined ones. Finally, significant advances are being made in the delivery systems of the genes, ranging from viral and non-viral vectors to tissue engineering scaffolds. Despite some public hesitation to gene therapy, its use has great potential to expand our ability to treat a variety of human bone and musculoskeletal disorders. It is conceivable that in the near future gene therapy can be utilized to induce bone formation in virtually any region of the body in a minimally invasive manner. As bone biology and gene therapy research progresses, the goal of successful human gene transfer for augmentation of bone regeneration draws nearer.

Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects

“…We previously demonstrated that BMP2, BMP6, and BMP9 can effectively upregulate OPN and OC expression in MSCs. 19,20,[24][25][26] As shown in Figure 4c, BMP2, BMP6, and BMP9 failed to induce any significant increases in OC expression in MG63, U2OS, and SaOS2 cells, although there was a small (o2.5-fold) but consistent induction of OPN expression in TE85 cells. Most OS lines, however, did not exhibit any significant increases in OPN expression upon osteogenic BMP stimulation (although there was a less than twofold increase in MG63 cells; Figure 4c).…”

“…We previously demonstrated that BMP2 and BMP9 can effectively induce ALP activity in MSCs. 19,20,[24][25][26] Our preliminary results indicated that most, if not all, of the TGFb/BMP types I and II receptors were expressed in the tested OS lines (data not shown). The four OS lines were stimulated with BMP2, BMP9, or GFP control, and their ALP activities were measured at days 5, 7, and 10.…”

“…We sought to determine whether ALP activity could be induced upon osteogenic BMP stimulation. BMP2, BMP6, BMP7, and BMP9 are the most potent BMPs to induce osteogenic differ- 19,20,[24][25][26] We first analyzed the basal expression of the four BMPs in OS lines. As shown in Figure 3a, BMP7 was relatively highly expressed in the four OS lines tested, whereas BMP2 expression was the lowest in these OS lines.…”

“…20,[22][23][24] We have analyzed the osteogenic potential of 14 human BMPs and found that BMP-2, 6, 9 are the most potent inducers of osteogenic differentiation both in vitro and in vivo. 19,20,[24][25][26] We have further demonstrated that osteogenic BMPs regulate a distinct set of target genes, such as Id HLH factors and connective tissue growth factor (CTGF)/CCN2, during osteogenic differentiation. 19,20,[27][28][29] Blockade of stem cell differentiation may lead to tumorigenesis.…”

Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector

“…2,41 The majority of these studies have used adenoviral vectors to infect cells either ex vivo or in vivo. These vectors, however, elicit an immune response and have a limited duration of expression.…”