PMID- 34796915
OWN - NLM
STAT- MEDLINE
DCOM- 20220504
LR  - 20220504
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 237
IP  - 3
DP  - 2022 Mar
TI  - Roburic acid attenuates osteoclastogenesis and bone resorption by targeting 
      RANKL-induced intracellular signaling pathways.
PG  - 1790-1803
LID - 10.1002/jcp.30642 [doi]
AB  - Excessive activity of osteoclasts contributes to skeletal diseases such as 
      osteoporosis and osteolysis. However, current drugs targeting osteoclast have 
      various deficiencies, placing natural compounds as substitutions of great 
      potential. Roburic acid (RA) is a triterpenoid exacted from Radix Gentianae 
      Macrophyllae, which exhibits inhibitory effects on inflammation and oxidation. By 
      employing an in vitro osteoclastogenesis model, this study investigates the 
      effects and mechanisms of RA on intracellular signaling induced by receptor 
      activator of nuclear factor-kappaB ligand (RANKL). As expected, RA at a concentration 
      scope from 1 to 10 muM dampened the osteoclast differentiation of bone marrow 
      macrophages (BMMs) but without cell toxicity. Interestingly, RA showed no effect 
      on osteoblastogenesis in vitro. Furthermore, RA mitigated F-actin ring formation, 
      hydroxyapatite resorption, and gene expression in osteoclasts. Mechanistically, 
      RA suppressed TNF receptor-associated factor 6 (TRAF6), the crucial adaptor 
      protein following RANKL-RANK binding. On the one hand, RA downregulated the 
      nuclear factor-kappaB (NF-kappaB) activity, extracellular regulated protein kinases (ERK) 
      phosphorylation, and calcium oscillations. On the other hand, RA upregulated the 
      antioxidative response element (ARE) response and the protein expression of heme 
      oxygenase (HO)-1. These upstream alterations eventually led to the suppression of 
      the nuclear factor of activated T cells 1 (NFATc1) activity and the expression of 
      proteins involved in osteoclastogenesis and bone resorption. Furthermore, by 
      using an ovariectomized (OVX) mice model, RA was found to have therapeutic 
      effects against bone loss. On account of these findings, RA could be used to 
      restrain osteoclasts for treating osteoporosis and other osteolytic diseases.
CI  - (c) 2021 Wiley Periodicals LLC.
FAU - Wang, Gang
AU  - Wang G
AUID- ORCID: 0000-0002-3769-0784
AD  - Department of Orthopaedics, First Affiliated Hospital, Guangzhou University of 
      Chinese Medicine, Guangzhou, China.
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
AD  - Guangzhou University of Chinese Medicine, Guangzhou, China.
FAU - Chen, Kai
AU  - Chen K
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
FAU - Ma, Chao
AU  - Ma C
AD  - Guangzhou University of Chinese Medicine, Guangzhou, China.
FAU - Wang, Chao
AU  - Wang C
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
FAU - Chen, Delong
AU  - Chen D
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
AD  - Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, 
      Netherlands.
FAU - He, Jianbo
AU  - He J
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
AD  - Department of Orthopaedics, Second Affiliated Hospital, Guangzhou University of 
      Chinese Medicine, Guangzhou, China.
FAU - Liu, Yuhao
AU  - Liu Y
AD  - Department of Orthopaedics, First Affiliated Hospital, Guangzhou University of 
      Chinese Medicine, Guangzhou, China.
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
FAU - Jiang, Tao
AU  - Jiang T
AD  - Department of Orthopaedics, Guangdong Second Traditional Chinese Medicine 
      Hospital, Guangzhou, China.
FAU - Yuan, Jinbo
AU  - Yuan J
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
FAU - Chen, Leilei
AU  - Chen L
AD  - Department of Orthopaedics, Third Affiliated Hospital, Guangzhou University of 
      Chinese Medicine, Guangzhou, China.
FAU - He, Wei
AU  - He W
AD  - Department of Orthopaedics, Third Affiliated Hospital, Guangzhou University of 
      Chinese Medicine, Guangzhou, China.
FAU - Xu, Jiake
AU  - Xu J
AUID- ORCID: 0000-0003-2021-8309
AD  - School of Biomedical Sciences, University of Western Australia, Perth, Western 
      Australia, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211119
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (NF-kappa B)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (RANK Ligand)
SB  - IM
MH  - Animals
MH  - *Bone Resorption/drug therapy/metabolism
MH  - Calcium Signaling
MH  - Cell Differentiation
MH  - Female
MH  - Humans
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - NFATC Transcription Factors/metabolism
MH  - Osteoclasts/metabolism
MH  - Osteogenesis
MH  - *Osteoporosis/drug therapy/metabolism
MH  - Ovariectomy
MH  - RANK Ligand/metabolism/pharmacology
OTO - NOTNLM
OT  - RANKL
OT  - TRAF6
OT  - osteoclast
OT  - roburic acid
EDAT- 2021/11/20 06:00
MHDA- 2022/05/06 06:00
CRDT- 2021/11/19 08:46
PHST- 2021/10/28 00:00 [revised]
PHST- 2021/07/12 00:00 [received]
PHST- 2021/11/09 00:00 [accepted]
PHST- 2021/11/20 06:00 [pubmed]
PHST- 2022/05/06 06:00 [medline]
PHST- 2021/11/19 08:46 [entrez]
AID - 10.1002/jcp.30642 [doi]
PST - ppublish
SO  - J Cell Physiol. 2022 Mar;237(3):1790-1803. doi: 10.1002/jcp.30642. Epub 2021 Nov 
      19.