Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration

Sihan Lin; Shi Yin; Junfeng Shi; Guangzheng Yang; Xutao Wen; Wenjie Zhang; Mingliang Zhou; Xinquan Jiang

doi:10.1016/j.bioactmat.2022.03.024

Orchestration of energy metabolism and osteogenesis by Mg²⁺ facilitates low-dose BMP-2-driven regeneration

Bioact Mater. 2022 Mar 24:18:116-127. doi: 10.1016/j.bioactmat.2022.03.024. eCollection 2022 Dec.

Authors

Sihan Lin^{1

2

3

4

5

6}, Shi Yin^{1

2

3

4

5

6}, Junfeng Shi^{1

2

3

4

5

6}, Guangzheng Yang^{1

2

3

4

5

6}, Xutao Wen⁷, Wenjie Zhang^{1

2

3

4

5

6}, Mingliang Zhou^{1

2

3

4

5

6}, Xinquan Jiang^{1

2

3

4

5

6}

Affiliations

¹ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
² College of Stomatology, Shanghai JiaoTong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
³ National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
⁴ National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
⁵ Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
⁶ Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
⁷ Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, No. 10 Shuangyong Road, Qingxiu District, Nanning, Guangxi, 530021, People's Republic of China.

Abstract

The clinical application of bone morphogenetic protein-2 (BMP-2) is limited by several factors, including ineffectiveness at low doses and severe adverse effects at high doses. To address these efficacy and safety limitations, we explored whether orchestration of energy metabolism and osteogenesis by magnesium ion (Mg²⁺) could reduce the dose and thereby improve the safety of BMP-2. Our results demonstrated that rapid metabolic activation triggered by BMP-2 was indispensable for subsequent osteogenesis. Moreover, inadequate metabolic stimulation was shown to be responsible for the ineffectiveness of low-dose BMP-2. Next, we identified that Mg²⁺, as an ''energy propellant", substantially increased cellular bioenergetic levels to support the osteogenesis via the Akt-glycolysis-Mrs2-mitochondrial axis, and consequently enhanced the osteoinductivity of BMP-2. Based on the mechanistic discovery, microgel composite hydrogels were fabricated as low-dose BMP-2/Mg²⁺ codelivery system through microfluidic and 3D printing technologies. An in vivo study further confirmed that rapid and robust bone regeneration was induced by the codelivery system. Collectively, these results suggest that this bioenergetic-driven, cost-effective, low-dose BMP-2-based strategy has substantial potential for bone repair.

Keywords: Biomaterials; Bone morphogenetic protein-2; Bone regeneration; Energy metabolism; Magnesium.