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

Bobin Mi¹, Yuan Xiong¹, Chenming Zhang¹, Wu Zhou¹, Lang Chen¹, Faqi Cao¹, Fenghua Chen², Zhi Geng², Adriana C. Panayi³, Yun Sun⁴, Lin Wang^2✉, Guohui Liu^1✉

1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology Wuhan, Hubei 430022, China.
2. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology Wuhan, Hubei 430022, China.
3. Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, USA.
4. Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology Wuhan, Hubei 430022, China.

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Citation:
Mi B, Xiong Y, Zhang C, Zhou W, Chen L, Cao F, Chen F, Geng Z, Panayi AC, Sun Y, Wang L, Liu G. SARS-CoV-2-induced Overexpression of miR-4485 Suppresses Osteogenic Differentiation and Impairs Fracture Healing. Int J Biol Sci 2021; 17(5):1277-1288. doi:10.7150/ijbs.56657. Available from https://www.ijbs.com/v17p1277.htm

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: SARS-CoV-2, miR-4485, Fracture, Differentiation, Osteoblast