Treatment of Osteonecrosis of the Femoral Head with VEGF₁₆₅ Transgenic Bone Marrow Mesenchymal Stem Cells in Mongrel Dogs

Abstract

We evaluated the efficacy of vascular endothelial growth factor 165 (VEGF₁₆₅) transgenic bone marrow mesenchymal stem cells (BMSCs) for the repair of early-stage osteonecrosis of the femoral head (ONFH) in mature mongrel dogs. This animal model was surgically established by femoral neck osteotomy and subsequent repinning. Twenty-seven dogs (54 hips) were divided into 3 equal-sized groups: a pCI-neo-VEGF₁₆₅ BMSC group, a pCI-neo BMSC group and a core decompression-alone group. The lipofectamine was used to introduce the VEGF₁₆₅ gene into the BMSCs. After core decompression, transgenic and non-transgenic autologous BMSCs were implanted. Therapeutic efficacy, including new bone formation and neovascularization in the femoral head, was examined by computed radiography, single-photon emission computed tomography, histological and histomorphometric analysis and immunofluorescent staining for von Willebrand factor in pathological sections. The femoral osteotomy site healed completely by the 4th week after the osteotomy surgery and regions of histologically evident osteonecrosis were found 12 weeks later. A regular arrangement of trabeculae and obvious bone regeneration were observed in the animals receiving implanted VEGF-transgenic BMSCs. The quantity of newly generated capillaries was significantly increased in the pCI-neo-VEGF₁₆₅ BMSC group, but there was no significant difference between the pCI-neo BMSC group and the core decompression-alone group. These results demonstrated that VEGF₁₆₅ transgenic autologous BMSCs enhanced bone reconstruction and blood vessel regeneration in the ONFH model. Compared with non-transgenic BMSCs, this approach could provide advanced benefits in the treatment of ONFH.

Stromal-Cell-Derived Factor (SDF) 1-Alpha Overexpression Promotes Bone Regeneration by Osteogenesis and Angiogenesis in Osteonecrosis of the Femoral Head

“…The findings of other studies suggested that the treatment with SC-79 (an Akt activator) and Vitamin K2 significantly improved the efficacy of osteogenesis in animals [17, 21]. Furthermore, transgenic overexpression of P-glycoprotein or VEGF165 in BMSCs significantly increased stem cell-induced osteogenesis as well [19, 20]. In addition, SDF-1 was found to be closely associated with osteogenesis and angiogenesis [49, 50].…”

“…Furthermore, P-glycoprotein (P-gp) overexpression was found to decrease the risk of steroid-induced ONFH [19]. The latter risk was alleviated by rifampicin likely through enhancing P-gp activity [20], whereas glucocorticoid-induced ONFH was successfully prevented by treatment with Vitamin K2 [21]. Moreover, augment the expression of BMP-2 and BFGF in BMSCs promoted bone repair of ONFH [22].…”

Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing

“…There are several etiologic risk factors such as trauma [3, 4], excessive corticosteroid use [5–7], excessive alcohol intake [8], Legg-Calve-Perthes disease [9, 10], etc. Debilitated blood supply to the femoral head commonly leads to necrosis and collapse of the femoral head [11]. In spite of various research efforts and trials, ONFH is still one of the most serious orthopedic problems.…”

Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head

“…Other factors affecting the choice of treatment are the extent and location of the necrotic area. 24,26 During the procedure for core decompression in patients with ONFH, the defect is filled with morsellized or synthetic bone grafts followed by graft impaction, which creates mechanical and biological conditions for graft incorporation. 21 All of the patients in this study were classified as having either stage I or stage II disease.…”