Melatonin Rescues the Ti Particle-Impaired Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells via the SIRT1/SOD2
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ORIGINAL RESEARCH
Melatonin Rescues the Ti Particle‑Impaired Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells via the SIRT1/SOD2 Signaling Pathway Yazhong Zhang1,2 · Xu Zhu1,2 · Genlin Wang1 · Liang Chen1 · Huilin Yang1,2 · Fan He1,2 · Jun Lin1 Received: 18 April 2020 / Accepted: 29 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Wear particles released by joint implants are a major cause of osteolysis around the prosthesis by negatively affecting bone reconstruction. Bone marrow mesenchymal stem cells (BMMSCs) stimulated by wear particles showed an impaired osteogenic potential. Melatonin has been shown beneficial effects on intracellular antioxidant functions and bone formation; however, whether it could restore the osteogenic potential of BMMSCs inhibited by wear particles was unknown. This study aimed to evaluate the protective effect of melatonin on the osteogenic capacity of BMMSCs exposed to titanium (Ti) wear particles and to investigated the underlying mechanisms involving intracellular antioxidant properties. When BMMSCs were exposed to Ti particles in vitro, melatonin treatment successfully improved the matrix mineralization and expression of osteogenic markers in BMMSCs, while decreasing the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. The protective effect of melatonin on osteolysis was validated in a Ti particle-exposed murine calvarial model. Meanwhile, silent information regulator type 1 (SIRT1) and intracellular antioxidant enzymes were significantly up-regulated, particularly superoxide dismutase 2 (SOD2), in melatonin-treated BMMSCs. Furthermore, inhibition of SIRT1 by EX527 completely counteracted the protective effect of melatonin on Ti particle-treated BMMSCs, evidenced by the reduced expression of SOD2, increased ROS and superoxide, and decreased osteogenic differentiation. These results demonstrated that melatonin restored the osteogenic potential and improved the antioxidant properties of BMMSCs through the SIRT1 signaling pathway. Our findings suggest that melatonin is a promising candidate for treating osteolysis induced by wear particles. Keywords Osteolysis · Ti particles · Melatonin · SIRT1 · SOD2
Introduction Aseptic periprosthetic osteolysis remains the leading cause of implant failure after total joint replacement [1, 2]. In the bone-prosthesis interface, wear particles stimulate a variety of cells that participate in the occurrence of osteolysis around the prosthesis [3]. For example, wear particles can * Fan He [email protected] * Jun Lin [email protected] 1
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, 215006 Suzhou, Jiangsu, China
Medical College, Orthopaedic Institute, Soochow University, No. 708 Renmin Road, 215007 Suzhou, Jiangsu, China
2
induce the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL1β), IL-6, and IL-17 around the prosthesis, and affect the activit
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