Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Kaichen Lai; Yue Xi; Xue Du; Zhiwei Jiang; Yongzheng Li; Tingben Huang; Xiaoyan Miao; Huiming Wang; Ying Wang; Guoli Yang

doi:10.3389/fcell.2020.00868

Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Front Cell Dev Biol. 2020 Sep 22:8:868. doi: 10.3389/fcell.2020.00868. eCollection 2020.

Authors

Kaichen Lai^{1

2}, Yue Xi^{1

2}, Xue Du^{1

2}, Zhiwei Jiang^{1

2}, Yongzheng Li^{1

2}, Tingben Huang^{1

2}, Xiaoyan Miao^{1

2}, Huiming Wang^{1

2}, Ying Wang^{1

2}, Guoli Yang^{1

2}

Affiliations

¹ The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China.

Abstract

Neural epidermal growth factor-like 1 protein (Nell-1) is first studied because of its association with human craniosynostosis. Nell-1 has been used to accelerate the process of fracture healing because of the osteoinductive ability in recent years. However, the role of Nell-1 during the process of osteointegration is unknown. Here we show that activation of Nell-1 in the BMSC sheet promotes osseointegration in vivo and in vitro. We found that overexpression of Nell-1 improved osteogenic differentiation and enhanced matrix mineralization of BMSCs through increasing expression of Runx2 and Osterix. Activation of Nell-1 up-regulated the expression ratio of OPG/RANKL, which might have a negative influence on osteoclast differentiation. Furthermore, we obtained BMSC sheet-implant complexes transfected with lentivirus overexpressing and interfering Nell-1 in in vivo study, and confirmed that overexpression of Nell-1 promoted new bone formation around the implant and increased the bone-implant contacting area percentage. Our results demonstrate that activation of Nell-1 improves implant osteointegration by regulating Runx2/Osterix axis and shows the potential of BMSC sheet-implant complexes in gene therapy.

Keywords: NELL-1; OPG-RANKL axis; Osterix; Runx2; cell sheet and tissue engineering; implant osseointegration.