PMID- 35342351
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20220415
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 18
IP  - 5
DP  - 2022
TI  - Melatonin reverses tumor necrosis factor-alpha-induced metabolic disturbance of 
      human nucleus pulposus cells via MTNR1B/Galphai2/YAP signaling.
PG  - 2202-2219
LID - 10.7150/ijbs.65973 [doi]
AB  - Background: Intervertebral disc degeneration (IDD), the main cause of low back 
      pain, is closely related to the inflammatory microenvironment in the nucleus 
      pulposus (NP). Tumor necrosis factor-alpha (TNF-alpha) plays an important role in 
      inflammation-related metabolic disturbance of NP cells. Melatonin has been proven 
      to regulate the metabolism of NP cells, but whether it can protect NP cells from 
      TNF-alpha-induced damage is still unclear. Therefore, this study aims to investigate 
      the role and specific mechanism of melatonin on regulating the metabolism of NP 
      cells in the inflammatory microenvironment. Methods: Western blotting, RT-qPCR 
      and immunohistochemistry were used to detect the expression of melatonin membrane 
      receptors (MTNR1A/B) and TNF-alpha in human NP tissues. In vitro, human primary NP 
      cells were treated with or without vehicle, TNF-alpha and melatonin. And the 
      metabolic markers were also detected by western blotting and RT-qPCR. The 
      activity of NF-kappaB signaling and Hippo/YAP signaling were assessed by western 
      blotting and immunofluorescence. Membrane receptors inhibitors, pathway 
      inhibitors, lentiviral infection, plasmids transfection and immunoprecipitation 
      were used to explore the specific mechanism of melatonin. In vivo, the rat IDD 
      model was constructed and melatonin was injected intraperitoneally to evaluate 
      its therapeutical effect on IDD. Results: The upregulation of TNF-alpha and 
      downregulation of melatonin membrane receptors (MTNR1A/B) were observed in 
      degenerative NP tissues. Then we demonstrated that melatonin could alleviate the 
      development of IDD in a rat model and reverse TNF-alpha-impaired metabolism of NP 
      cells in vitro. Further investigation revealed that the protective effects of 
      melatonin on NP cells mainly rely on MTNR1B, which subsequently activates Galphai2 
      protein. The activation of Galphai2 could upregulate the yes-associated protein (YAP) 
      level, resulting in anabolic enhancement of NP cells. In addition, 
      melatonin-mediated YAP upregulation increased the expression of IkappaBalpha and 
      suppressed the TNF-alpha-induced activation of the NF-kappaB pathway, thereby inhibiting 
      the catabolism of NP cells. Conclusions: Our results revealed that melatonin can 
      reverse TNF-alpha-impaired metabolism of NP cells via the MTNR1B/Galphai2/YAP axis and 
      suggested that melatonin can be used as a potential therapeutic drug in the 
      treatment of IDD.
CI  - (c) The author(s).
FAU - Qiu, Xianjian
AU  - Qiu X
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Liang, Tongzhou
AU  - Liang T
AD  - Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, 
      Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
FAU - Wu, Zizhao
AU  - Wu Z
AD  - Department of Orthopedic Surgery, The Third Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Zhu, Yuanxin
AU  - Zhu Y
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Gao, Wenjie
AU  - Gao W
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Gao, Bo
AU  - Gao B
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Qiu, Jincheng
AU  - Qiu J
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Wang, Xudong
AU  - Wang X
AD  - Department of Orthopedic Surgery, The First Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Chen, Taiqiu
AU  - Chen T
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Deng, Zhihuai
AU  - Deng Z
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Li, Pengfei
AU  - Li P
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Chen, Yanbo
AU  - Chen Y
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Zhou, Hang
AU  - Zhou H
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Peng, Yan
AU  - Peng Y
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Xu, Caixia
AU  - Xu C
AD  - Research Centre for Translational Medicine, The First Affiliated Hospital of Sun 
      Yat-sen University, Guangzhou, Guangdong, China.
FAU - Su, Peiqiang
AU  - Su P
AD  - Department of Orthopedic Surgery, The First Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Liang, Anjing
AU  - Liang A
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Huang, Dongsheng
AU  - Huang D
AD  - Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220306
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - 0 (MTNR1B protein, human)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptor, Melatonin, MT2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunit, Gi2)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - GTP-Binding Protein alpha Subunit, Gi2/metabolism/pharmacology
MH  - Humans
MH  - *Intervertebral Disc Degeneration/metabolism
MH  - *Melatonin/metabolism/pharmacology/therapeutic use
MH  - NF-kappa B/metabolism
MH  - *Nucleus Pulposus/metabolism
MH  - Rats
MH  - Receptor, Melatonin, MT2/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC8935230
OTO - NOTNLM
OT  - MTNR1B
OT  - TNF-alpha
OT  - intervertebral disc degeneration
OT  - melatonin
OT  - nucleus pulposus cells
OT  - yes-associated protein.
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2022/03/29 06:00
MHDA- 2022/04/16 06:00
PMCR- 2022/01/01
CRDT- 2022/03/28 05:30
PHST- 2021/08/15 00:00 [received]
PHST- 2022/02/09 00:00 [accepted]
PHST- 2022/03/28 05:30 [entrez]
PHST- 2022/03/29 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - ijbsv18p2202 [pii]
AID - 10.7150/ijbs.65973 [doi]
PST - epublish
SO  - Int J Biol Sci. 2022 Mar 6;18(5):2202-2219. doi: 10.7150/ijbs.65973. eCollection 
      2022.