Abstract
Bone morphogenetic proteins (BMPs) have been clinically applied for induction of bone formation in musculoskeletal disorders such as critical-sized bone defects, nonunions, and spinal fusion surgeries. However, the use of supraphysiological doses of BMP caused adverse events, which were sometimes life-threatening. Therefore, safer treatment strategies for bone regeneration have been sought for decades. Systemic administration of a potent selective antagonist of retinoic acid nuclear receptor gamma (RARγ) (7C) stimulated BMP-induced ectopic bone formation. In this study, we developed 7C-loaded poly lactic nanoparticles (7C-NPs) and examined whether local application of 7C enhances BMP-induced bone regeneration. The collagen sponge discs that absorbed recombinant human (rh) BMP-2 were implanted into the dorsal fascia of young adult mice to induce ectopic bone. The combination of rhBMP-2 and 7C-NP markedly increased the total bone volume and thickness of the bone shell of the ectopic bone in a dose-dependent manner compared to those with rhBMP-2 only. 7C stimulated sulfated proteoglycan production, expression of chondrogenic marker genes, and Sox9 reporter activity in both chondrogenic cells and MSCs. The findings suggest that selective RARγ antagonist 7C or the related compounds potentiate the bone inductive ability of rhBMP-2, as well as support any future research to improve the BMP-2 based bone regeneration procedures in a safe and efficient manner.
Highlights
Treatment for large bone defects caused by tumor resection or complex fracture remains a challenge in the field of orthopedics
We evaluated the therapeutic potential of 7C as an enhancer of Bone morphogenetic proteins (BMPs)-2 in a mouse ectopic bone formation model and characterized its action in the process of endochondral ossification
MRNAs were prepared from the pellets of the BMP 1.5 μg and BMP 1.5 μg + 7C groups (n = 12 per each group), and the gene expression levels of inflammatory cytokines were measured by real-time polymerase chain reaction
Summary
Treatment for large bone defects caused by tumor resection or complex fracture remains a challenge in the field of orthopedics. Autogenous bone grafting has been the gold standard, but the application is hampered by limited availability and donor site morbidity (Laurie et al, 1984; Betz, 2002). RARγ Action on Bone Formation been attracting attention as a novel osteoinductive grafting material (Urist, 1965; Wozney et al, 1988; Burkus et al, 2002; Lo et al, 2012). It is challenging to strike a balance between ensuring sufficient BMP bone-inducing capacity and suppressing the side effects of BMP. In a study of human open tibial fractures, the rate of non-union was increased by more than 40% after low-dose BMP treatment (Govender et al, 2002).
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