SARS-CoV-2-induced Overexpression of miR-4485 Suppresses Osteogenic Differentiation and Impairs Fracture Healing

Int J Biol Sci. 2021 Mar 25;17(5):1277-1288. doi: 10.7150/ijbs.56657. eCollection 2021.

Abstract

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the cell entry point for SARS-CoV-2. Although ACE2 receptors are present in the bone marrow, the effects of SARS-CoV-2 on the biological activity of bone tissue have not yet been elucidated. In the present study we sought to investigate the impact of SARS-CoV-2 on osteoblastic activity in the context of fracture healing. MicroRNA-4485 (miR-4485), which we found to be upregulated in COVID-19 patients, negatively regulates osteogenic differentiation. We demonstrate this effect both in vitro and in vivo. Moreover, we identified the toll-like receptor 4 (TLR-4) as the potential target gene of miR-4485, and showed that reduction of TLR-4 induced by miR-4485 suppresses osteoblastic differentiation in vitro. Taken together, our findings highlight that up-regulation of miR-4485 is responsible for the suppression of osteogenic differentiation in COVID-19 patients, and TLR-4 is the potential target through which miR-4485 acts, providing a promising target for pro-fracture-healing and anti-osteoporosis therapy in COVID-19 patients.

Keywords: Differentiation; Fracture; Osteoblast; SARS-CoV-2; miR-4485.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiotensin-Converting Enzyme 2 / metabolism
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Cell Differentiation*
  • Female
  • Fracture Healing*
  • Humans
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Osteogenesis*
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / physiology*
  • Toll-Like Receptor 4 / metabolism

Substances

  • MIRN4485 microRNA, human
  • MicroRNAs
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2