Melatonin Improves the Resistance of Oxidative Stress-Induced Cellular Senescence in Osteoporotic Bone Marrow Mesenchymal Stem Cells.

Weikai Chen,Tao Liu,Xi Chen,Fan He,Xinfeng Zhou,Chao Gu,Wanjin Qin,Liang Chen,Nanning Lv,Angela Carley Chen,Hao Liu,Huilin Yang,Tullia Maraldi

doi:10.1155/2022/7420726

Abstract

Accumulation of senescent bone marrow-derived mesenchymal stem cells (BMMSCs) has led to an age-related bone loss. However, the role of stem cell senescence in estrogen deficiency-induced osteoporosis remains elusive. Though melatonin plays a vital role in bone metabolism regulation, the underlying mechanisms of melatonin-mediated antiosteoporosis are partially elucidated. Therefore, this study purposed to explore (1) whether estrogen deficiency causes cellular senescence of BMMSCs, and if so, (2) the potential of melatonin in preventing bone loss via senescence signaling inhibition. BMMSCs derived from ovariectomized (OVX) rats (OVX BMMSCs) showed an impaired osteogenic capacity, albeit having comparable levels of senescence biomarkers than the sham cells. When exposed to low levels of hydrogen peroxide (H2O2), OVX BMMSCs rapidly exhibited senescence-associated phenotypes such as the increased activity of senescence-associated β-galactosidase (SA-β-gal) and upregulation of cell cycle inhibitors. Notably, the in vitro treatment with melatonin hindered H2O2-induced senescence in OVX BMMSCs and restored their osteogenic capacity. Treatment with either SIRT1 inhibitor (sirtinol) or melatonin receptor antagonists (luzindole and 4-P-PDOT) eliminated melatonin protective effects, thus indicating its potential in preventing stem cell senescence via SIRT1 activation through the melatonin membrane receptors. Following in vivo intravenous administration with melatonin, it successfully protected the bone microstructure and preserved the antisenescence property of BMMSCs in OVX rats. Collectively, our findings demonstrated that melatonin protected against estrogen deficiency-related bone loss by improving the resistance of BMMSCs to cellular senescence. Therefore, melatonin-mediated antisenescence effect on stem cells provides vital information to facilitate the development of a novel and effective strategy for treating postmenopausal OP.

Highlights

Estrogen deficiency is a major cause of postmenopausal osteoporosis (OP) that leads to an imbalance in osteoblastmediated bone formation and osteoclast-mediated bone resorption [1]
On H2O2 exposure with the same concentrations (e.g., 68:5 ± 6:9% vs. 20:9 ± 2:8% at 100 μM), the percentage of β-gal-positive cells in the OVX group were markedly higher than the sham group
Real-time PCR showed that exposure to H2O2 significantly upregulated the transcript levels of P16, P21, and P53 by 1.0-fold, 2.3-fold, and 1.5-fold in OVX Bone marrow-derived mesenchymal stem cells (BMMSCs), respectively, while the mRNA level of Sirt1 was decreased by 73.1% (Figure 1(c))

Summary

Introduction

Estrogen deficiency is a major cause of postmenopausal osteoporosis (OP) that leads to an imbalance in osteoblastmediated bone formation and osteoclast-mediated bone resorption [1]. Bone marrow-derived mesenchymal stem cells (BMMSCs), the progenitor cells of osteoblasts, play a crucial role in mediating bone homeostasis. The senescent stem cells accumulated in the bone marrow with age are considered to be responsible for the age-related bone loss [3]. The accumulation of P16 triggers the onset of cellular senescence [6], while the elimination of P16-positive senescent cells in aged mice potentially promotes bone formation [7]. The role of stem cell senescence in estrogen deficiency-induced OP remains controversial. An emerging study showed contrary findings that elimination of senescent cells failed to rescue bone loss in OVX mice, indicating an independent role of cellular senescence in estrogen deficiency-induced OP [9]

Methods

Results

Conclusion