Abstract
The present study evaluated the protective effects of melatonin in ethanol (EtOH)-induced senescence and osteoclastic differentiation in human periodontal ligament cells (HPDLCs) and cementoblasts and the underlying mechanism. EtOH increased senescence activity, levels of reactive oxygen species (ROS) and the expression of cell cycle regulators (p53, p21 and p16) and senescence-associated secretory phenotype (SASP) genes (interleukin [IL]-1β, IL-6, IL-8 and tumor necrosis factor-α) in HPDLCs and cementoblasts. Melatonin inhibited EtOH-induced senescence and the production of ROS as well as the increased expression of cell cycle regulators and SASP genes. However, it recovered EtOH-suppressed osteoblastic/cementoblastic differentiation, as evidenced by alkaline phosphatase activity, alizarin staining and mRNA expression levels of Runt-related transcription factor 2 (Runx2) and osteoblastic and cementoblastic markers (glucose transporter 1 and cementum-derived protein-32) in HPDLCs and cementoblasts. Moreover, it inhibited EtOH-induced osteoclastic differentiation in mouse bone marrow–derived macrophages (BMMs). Inhibition of protein never in mitosis gene A interacting-1 (PIN1) by juglone or small interfering RNA reversed the effects of melatonin on EtOH-mediated senescence as well as osteoblastic and osteoclastic differentiation. Melatonin blocked EtOH-induced activation of mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and Nuclear factor of activated T-cells (NFAT) c-1 pathways, which was reversed by inhibition of PIN1. This is the first study to show the protective effects of melatonin on senescence-like phenotypes and osteoclastic differentiation induced by oxidative stress in HPDLCs and cementoblasts through the PIN1 pathway.
Highlights
Tooth loss increases with age and this is primarily thought to be due to the breakdown of periodontal tissue around natural teeth as a result of periodontitis [1]
Periodontal disease is characterized by an inflammatory reaction of periodontal tissue that leads to the progressive destruction of tooth-associated structures including alveolar bone, periodontal ligament (PDL) and cementum [2]
Our results show that subcytotoxic concentrations (10–50 mM) of EtOH induce immature cellular senescence in human periodontal ligament cells (HPDLCs) and cementoblasts, which was confirmed by growth arrest, altered cell morphology, increased β-gal activity and reactive oxygen species (ROS) levels and overexpression of senescence-associated genes
Summary
Tooth loss increases with age and this is primarily thought to be due to the breakdown of periodontal tissue around natural teeth as a result of periodontitis [1]. PDL cells (PDLCs) located between the tooth cementum and bone play a major role in alveolar bone metabolism in periodontal health and disease because of their ability to secrete factors that regulate the homeostasis of connective and osseous tissue, including inflammatory cytokines and major osteoblast or osteoclast regulators [3,4,5,6]. Melatonin decreases the expression of inflammatory and apoptotic markers [24] and improves age-related insulin resistance [25] and neurodegenerative disease in a senescence-accelerated mouse model [26]. It efficiently inhibits anticancer drug-induced premature senescence in A549 lung cancer cells [27]. We investigated the effects and underlying mechanism of action of melatonin in ethanol (EtOH)-stimulated premature senescence and osteoclastic differentiation in human PDLCs and cementoblasts
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