Adenovirus‐mediated VEGF‐A gene transfer induces bone formationin vivo

Abstract

Osteoporosis is a major problem in elderly population. We tested the hypothesis whether vascular endothelial growth factor (VEGF-A) gene transfer is an appropriate way to enhance bone formation and recruitment of osteoblasts in vivo. Adenovirus vectors containing VEGF-A or lacZ cDNAs (1.4x10(10) pfu) were injected locally into right distal femurs of New Zealand White rabbits. Saline was injected into all contralateral distal femurs. One and three weeks after the gene transfers femurs were collected for analyses. X-Gal staining showed that up to 20% of the bone marrow cells were transfected although gene transfer also resulted in biodistribution of the vector and expression of the transgene in liver and spleen. Trabecular bone hard tissue histomorphometry of the distal femurs was performed to analyze the effect of gene transfer on bone turnover. When compared with unilateral lacZ transfected trabecular bone at one-week and three-week time points, VEGF-A gene transfer significantly increased bone formation parameters, such as osteoblast number, osteoid volume, and bone volume. Also, bone resorption surface was greatly reduced. It is concluded that injection of adenovirus vector can transfect bone marrow cells in vivo with a relatively high efficiency. Our results suggest that adenovirus-mediated VEGF-A gene transfer induces bone formation via increasing osteoblast activity and may be useful for the treatment of osteoporosis and other diseases that require efficient osteogenic therapy.

Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

“…Inhibition of VEGF activity led to fewer primary trabeculae, and thick and shortened secondary trabeculae, suggesting defects in bone formation. This is consistent with previous studies showing that VEGF regulates osteoblast differentiation and function (Hiltunen et al, 2003;Maes et al, 2002;Midy and Plouet, 1994;Street et al, 2002;Zelzer et al, 2002). However, inhibition of all MMPs resulted in both the absence of primary trabeculae and a thick mass of secondary trabeculae that seemed to have fused together; this suggests defects in both bone formation and resorption.…”

“…The improved angiogenesis and ossification by exogenous VEGF may negate the need for compensatory recruitment of ECM-resorbing cells. However, VEGF also affects the formation and/or function of osteoblasts (Hiltunen et al, 2003;Maes et al, 2002;Street et al, 2002;Zelzer et al, 2002), which are known to modulate osteoclast formation. Thus, exogenous VEGF may also reduce osteoclast number through its effects on osteoblasts.…”

Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair

“…Accordingly, VEGF is important during fracture healing. Inhibition of VEGF activity disrupts the repair process and results in nonunions, whereas treatment with exogenous VEGF promotes bone formation and angiogenesis in several animal models (9)(10)(11)(12). The VEGF homolog placental growth factor (PlGF) has been shown to have a more relevant role in disease than in development (13).…”

Prothymosin α Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis

“…In this study, we showed that AdProT⌬NLS downregulated the MIP-1␣ promoter activity induced by TNF-␣ in rat synovial fibroblasts, resulting in lower levels of MIP-1␣, IL-1␤, and TNF-␣, as well as decreased macrophage infiltration in the ankle joints of rats with CIA. Adenoviral vectors have been used for gene delivery to osteoblastic cell lines, achieving ϳ90% transfection efficiency with MOI of 500 (42). Osteoblasts can synthesize TNF-␣, IL-1␤, IL-6, and IL-8 in response to a variety of stimuli, such as LPS (43)(44)(45)(46).…”