Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein.
Tumor necrosis factor-alpha (TNFα) plays a pivotal role in inflammation-related osteoporosis through the promotion of bone resorption and suppression of bone formation. Numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, but they offer few benefits to bone formation, which is what is needed by patients with severe bone loss. Melatonin, which can exert both anti-inflammatory and pro-osteogenic effects, shows promise in overcoming TNFα-inhibited osteogenesis and deserves further research. This study demonstrated that melatonin rescued TNFα-inhibited osteogenesis of human mesenchymal stem cells and that the interactions between SMURF1 and SMAD1 mediated the crosstalk between melatonin signaling and TNFα signaling. Additionally, melatonin treatment was found to downregulate TNFα-induced SMURF1 expression and then decrease SMURF1-mediated ubiquitination and degradation of SMAD1 protein, leading to steady bone morphogenetic protein-SMAD1 signaling activity and restoration of TNFα-impaired osteogenesis. Thus, melatonin has prospects for treating osteoporosis caused by inflammatory factors due to its multifaceted functions on regulation of bone formation, bone resorption, and inflammation. Further studies will focus on unveiling the specific mechanisms by which melatonin downregulates SMURF1 expression and confirming the clinical therapeutic value of melatonin in the prevention and therapy of bone loss associated with inflammation.
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Chengjie
C
Lian
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Zizhao
Z
Wu
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Bo
B
Gao
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Yan
Y
Peng
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Anjing
A
Liang
Research Centre for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Caixia
C
Xu
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Lei
L
Liu
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Xianjian
X
Qiu
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Junjun
J
Huang
Department of Orthopedics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Hang
H
Zhou
Department of Orthopedics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Yifeng
Y
Cai
Department of Orthopedics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. supq@mail.sysu.edu.cn.
Peiqiang
P
Su
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. huangdongshen18@hotmail.com.
Dongsheng
D
Huang
D002478:Cells, Cultured; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051898:Smad1 Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*
C497399:SMAD1 protein, human; D051898:Smad1 Protein; D014409:Tumor Necrosis Factor-alpha; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D008550:Melatonin
SMAD1; SMURF1; human mesenchymal stem cells; melatonin; osteogenesis; tumor necrosis factor-alpha