title: Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway.
abstract: Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals. Melatonin alleviated titanium particle-induced depression of osteoblastic differentiation and mineralization in mMSCs. Mechanistically, melatonin was found to reduce the degradation of β-catenin, levels of which were decreased in presence of titanium particles both in vivo and in vitro. To further ensure whether the protective effect of melatonin was mediated by the Wnt/β-catenin signaling pathway, ICG-001, a selective β-catenin inhibitor, was added to the melatonin-treated groups and was found to attenuate the effect of melatonin on mMSC mineralization. We also demonstrated that melatonin modulated the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin via activation of Wnt/β-catenin signaling pathway. These findings strongly suggest that melatonin represents a promising candidate in the treatment of PPO.
  
  
  
  Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/β-catenin signaling pathway and enhancing osteogenic differentiation. Meanwhile, the ability of melatonin to modulate the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin mediated by Wnt/β-catenin signaling pathway, thereby suppressing osteoclastogenesis, may be implicated in the protective effects of melatonin on titanium-particle-induced bone resorption. These results suggested that melatonin can be considered as a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis.
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Zichuan
authors.initials: Z
authors.lastname: Ping
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Xuanyang
authors.initials: X
authors.lastname: Hu
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Shi
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Tao
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Xiexing
authors.initials: X
authors.lastname: Wu
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Zhenyang
authors.initials: Z
authors.lastname: Hou
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Soochow University, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The First Affiliated Hospital of Soochow University, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Yang
authors.affiliation: The First Affiliated Hospital of Soochow University, China. Electronic address: xuyaozeng@163.com.
authors.forename: Yaozeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Zhangjiagang Hospital of Traditional Chinese Medicine, China. Electronic address: wangzzr@126.com.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Soochow University, China. Electronic address: szgengdc@163.com.
authors.forename: Dechun
authors.initials: D
authors.lastname: Geng
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D012886:Skull / Q000473:pathology; D014025:Titanium / Q000009:adverse effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D051176:beta Catenin; D014025:Titanium; D008550:Melatonin
keywords: Bone regeneration; Bone resorption; Melatonin; Peri-prosthetic osteolysis; Wear debris; Wnt/β-catenin signaling