MicroRNA for bone regeneration

Bone formation is mediated by biochemical signaling pathways that regulate the behavior of osteoblasts and osteoclasts. The bone tissue is continuously being remodeled - aged bone is reabsorbed, while new bone is ossified.1


Gene regulation and osteoblast differentiation are essential factors for bone regeneration. Several studies showed that microRNAs (miRNAs) are imperative epigenetic factors that control many aspects of bone development and repair. These non-coding RNA fragments regulate gene expression at the post-transcriptional level, playing an essential role in other cellular processes, such as differentiation, proliferation, and apoptosis. 2 3


Figure 1: Steps involved in miRNA-based bone regeneration. 4



It is believed that manipulation of microRNAs may allow the development of bone regeneration therapy. Therapeutic trials using microRNA for bone diseases are already being performed in animal models. With the high level of life expectancy of the general population, there is a growing need to repair bone defects, such as osteoporosis. Therefore, it is necessary to develop efficient alternatives to conventional treatments, such as autologous or allogeneic bone grafts, as they present some disadvantages related to limited availability, possibility of infection and severe postoperative pain. 2 3



As a bone regeneration strategy, different hydrogel-based scaffolds can be developed to release miRNA locally to surrounding cells, providing a platform for cell migration, adhesion, and differentiation. This technique is quite advantageous, mainly compared to the preparation of scaffold-free miRNA nanoparticles. These particles are quickly eliminated from the desired sites after in vivo injection due to their small size and discontinuous release in the scaffold-free strategy. 5


Figure 2: Schematic diagram of RNA-based scaffolds used for bone regeneration. 5


Chang et al. (2018) performed an analysis of differentially expressed miRNAs in bone marrow-derived stem cells (BMSC) during in vitro differentiation of osteoblast. The team validated the regulatory effects of miRNAs on the differentiation of osteoblasts and identified 15 miRNAs, mainly miR-222 and miR-423, that are important regulators of osteoblastogenesis. In addition, the targeting of miRNAs to increase bone tissue regeneration was also tested. Scaffolds that were functionalized with miRNA nano-carriers increased osteoblastogenesis in 3D culture. Several additional miRNAs exerted additive osteoinductive effects on BMSC differentiation, suggesting that pools of miRNAs supplied locally from an implanted scaffold are a promising approach for bone regeneration. 6





REFERENCES


1. Kaur, T., Kapila, R. & Kapila, S. MicroRNAs as Next Generation Therapeutics in Osteoporosis. in Clinical Implementation of Bone Regeneration and Maintenance (eds. Barbeck, M., Rosenberg, N., Rider, P., Kačarević, Ž. P. & Jung, O.) (IntechOpen, 2021).

2. Nakasa, T., Yoshizuka, M., Andry Usman, M., Elbadry Mahmoud, E. & Ochi, M. MicroRNAs and Bone Regeneration. Curr. Genomics 16, 441–452 (2015).

3. Hensley, A. P. & McAlinden, A. The role of microRNAs in bone development. Bone 143, 115760 (2021).

4. Fang, S., Deng, Y., Gu, P. & Fan, X. MicroRNAs regulate bone development and regeneration. Int. J. Mol. Sci. 16, 8227–8253 (2015).

5. Leng, Q., Chen, L. & Lv, Y. RNA-based scaffolds for bone regeneration: application and mechanisms of mRNA, miRNA and siRNA. Theranostics 10, 3190–3205 (2020).

6. Chang, C.-C. et al. Global MicroRNA Profiling in Human Bone Marrow Skeletal-Stromal or Mesenchymal-Stem Cells Identified Candidates for Bone Regeneration. Mol. Ther. 26, 593–605 (2018).