Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition

Wei Zhang; Xingzhi Zhou; Weiduo Hou; Erman Chen; Chenyi Ye; Mo Chen; Qian Lu; Xiaohua Yu; Weixu Li

doi:10.1016/j.bioactmat.2022.04.017

Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition

Bioact Mater. 2022 May 2:19:429-443. doi: 10.1016/j.bioactmat.2022.04.017. eCollection 2023 Jan.

Authors

Wei Zhang^{1

2}, Xingzhi Zhou^{1

2}, Weiduo Hou^{1

2}, Erman Chen^{1

2}, Chenyi Ye^{1

2}, Mo Chen³, Qian Lu^{2

4}, Xiaohua Yu^{1

2}, Weixu Li^{1

2}

Affiliations

¹ Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, China.
² Research Institute of Orthopaedics, Zhejiang University, 310009, Hangzhou, China.
³ Department of Rheumatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, China.
⁴ Department of Orthopedics, Huzhou Hospital, Zhejiang University, China.

Abstract

The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (β-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.

Keywords: ALP, Alkaline phosphatase; BMM, Bone marrow-derived macrophage; BMSCs, Bone marrow-derived mesenchymal stem cells; CCK-8, Cell Counting Kit-8; FBS, Fetal bovine serum; FTIR, Fourier transform infrared; IF, Immunofluorescence; Mineral coating; OPN, Osteopontin; OVX, Ovariectomy; Osteoblast; Osteoclast; Osteoporosis; P1NP, Pro-collagen type 1N-terminal peptide; RT-qPCR, Quantitative real-time polymerase chain reaction; SBF, Simulated body fluid; SEM, Scanning electron microscopy; SIRT1; WB, Western blot; XRD, X-ray diffraction; micro-CT, Microcomputed tomography; siRNA, Small interfering RNA.