Enhancement of bone regeneration by coadministration of angiogenic and osteogenic factors using messenger RNA

Inflammation and Regeneration

Research Article

Kosuke Nozaki¹  Noriyuki Wakabayashi¹  Yuta Fukushima²  Hideyuki Nakanishi²  Keiji Itaka³  Maorui Zhang⁴  Jia Deng⁵ 

[1]Department of Advanced Prosthodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1138549, Tokyo, Japan

[2]Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 1010062, Tokyo, Japan

[3]Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 1010062, Tokyo, Japan

[4]Clinical Biotechnology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, 565-0871, Osaka, Japan

[5]Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 1010062, Tokyo, Japan

[6]Department of Advanced Prosthodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1138549, Tokyo, Japan

[7]Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, 646000, Luzhou, People’s Republic of China

[8]Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 1010062, Tokyo, Japan

[9]Department of Masticatory Function and Health Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 113-8549, Tokyo, Japan

关键词: Bone regeneration;    Angiogenesis;    mRNA medicine;    Vascular endothelial growth factor;    Runt-related transcription factor 2;    Mandible bone defect;    Polyplex nanomicelle;   

DOI  :  10.1186/s41232-023-00285-3

 received in 2023-03-01, accepted in 2023-06-08,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundBone defects remain a challenge today. In addition to osteogenic activation, the crucial role of angiogenesis has also gained attention. In particular, vascular endothelial growth factor (VEGF) is likely to play a significant role in bone regeneration, not only to restore blood supply but also to be directly involved in the osteogenic differentiation of mesenchymal stem cells. In this study, to produce additive angiogenic-osteogenic effects in the process of bone regeneration, VEGF and Runt-related transcription factor 2 (Runx2), an essential transcription factor for osteogenic differentiation, were coadministered with messenger RNAs (mRNAs) to bone defects in the rat mandible.MethodsThe mRNAs encoding VEGF or Runx2 were prepared via in vitro transcription (IVT). Osteogenic differentiation after mRNA transfection was evaluated using primary osteoblast-like cells, followed by an evaluation of the gene expression levels of osteogenic markers. The mRNAs were then administered to a bone defect prepared in the rat mandible using our original cationic polymer-based carrier, the polyplex nanomicelle. The bone regeneration was evaluated by micro-computerized tomography (μCT) imaging, and histologic analyses.ResultsOsteogenic markers such as osteocalcin (Ocn) and osteopontin (Opn) were significantly upregulated after mRNA transfection. VEGF mRNA was revealed to have a distinct osteoblastic function similar to that of Runx2 mRNA, and the combined use of the two mRNAs resulted in further upregulation of the markers. After in vivo administration into the bone defect, the two mRNAs induced significant enhancement of bone regeneration with increased bone mineralization. Histological analyses using antibodies against the Cluster of Differentiation 31 protein (CD31), alkaline phosphatase (ALP), or OCN revealed that the mRNAs induced the upregulation of osteogenic markers in the defect, together with increased vessel formation, leading to rapid bone formation.ConclusionsThese results demonstrate the feasibility of using mRNA medicines to introduce various therapeutic factors, including transcription factors, into target sites. This study provides valuable information for the development of mRNA therapeutics for tissue engineering.

【 授权许可】

CC BY   
© The Author(s) 2023

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