PMID- 31837247
OWN - NLM
STAT- MEDLINE
DCOM- 20210513
LR  - 20210513
IS  - 1742-4658 (Electronic)
IS  - 1742-464X (Linking)
VI  - 287
IP  - 14
DP  - 2020 Jul
TI  - Forkhead box C1 promotes the pathology of osteoarthritis by upregulating 
      beta-catenin in synovial fibroblasts.
PG  - 3065-3087
LID - 10.1111/febs.15178 [doi]
AB  - Osteoarthritis (OA) is a joint disease characterized by articular cartilage 
      degeneration, and no effective treatment is available. The OA classification has 
      shifted from a cartilage-only disease to a whole-joint disease, and the synovial 
      membrane plays an important role. Therefore, studies are needed to identify 
      additional genes that regulate the pathological changes in the synovial membrane 
      to develop a promising therapeutic strategy for OA. Here, we validated that the 
      expression of forkhead box protein C1 (FoxC1) and beta-catenin was upregulated in OA 
      synovial membranes and synovial fibroblasts (SFs). Gain- and loss-of-function 
      studies revealed that FoxC1 overexpression promoted, whilst silencing inhibited 
      OA synovial fibroblast (OASF) proliferation and pro-inflammatory cytokine 
      [interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha)] 
      production. FoxC1 overexpression increased beta-catenin mRNA, total and nuclear 
      protein expression in OASFs and upregulated a disintegrin and metalloproteinase 
      with thrombospondin motif 5 (ADAMTS-5), fibronectin, matrix metalloproteinase 3 
      (MMP3) and matrix metalloproteinase 13 (MMP13) mRNA and total protein expression 
      in OASFs. Conversely, FoxC1 knockdown reduced beta-catenin mRNA, total and nuclear 
      protein expression in OASFs and reduced ADAMTS-5, fibronectin, MMP3 and MMP13 
      mRNA and total protein expression in OASFs. beta-catenin mediates FoxC1-induced 
      pathological changes (proliferation, catabolic regulation and inflammation) in 
      OASFs. MicroRNA-200a-3p (miR-200a-3p) binds to the 3'-UTR of FoxC1 and mediates 
      FoxC1 expression. Intra-articular FoxC1-specific siRNA transfection hindered OA 
      development in mice. Therefore, our results demonstrate the key role FoxC1 plays 
      in vivo and in vitro in OA synovial pathology, possibly identifying a potential 
      novel therapeutic target for OA.
CI  - (c) 2019 Federation of European Biochemical Societies.
FAU - Wang, Jun
AU  - Wang J
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Wang, Yin
AU  - Wang Y
AD  - Department of Plastic Surgery, The Fourth Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Zhang, Hui
AU  - Zhang H
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Gao, Weilu
AU  - Gao W
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Lu, Ming
AU  - Lu M
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Liu, Wendong
AU  - Liu W
AD  - Department of Radiology, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Li, Yetian
AU  - Li Y
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
FAU - Yin, Zongsheng
AU  - Yin Z
AUID- ORCID: 0000-0002-1931-913X
AD  - Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical 
      University, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191229
PL  - England
TA  - FEBS J
JT  - The FEBS journal
JID - 101229646
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (FOXC1 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (MIRN200 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Female
MH  - Fibroblasts/metabolism/*pathology
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics
MH  - Osteoarthritis/genetics/metabolism/*pathology
MH  - Synovial Membrane/metabolism/*pathology
MH  - Up-Regulation
MH  - Young Adult
MH  - beta Catenin/genetics/*metabolism
OTO - NOTNLM
OT  - FoxC1
OT  - Osteoarthritis
OT  - miR-200a-3p
OT  - beta-catenin
EDAT- 2019/12/15 06:00
MHDA- 2021/05/14 06:00
CRDT- 2019/12/15 06:00
PHST- 2019/09/23 00:00 [received]
PHST- 2019/11/17 00:00 [revised]
PHST- 2019/12/12 00:00 [accepted]
PHST- 2019/12/15 06:00 [pubmed]
PHST- 2021/05/14 06:00 [medline]
PHST- 2019/12/15 06:00 [entrez]
AID - 10.1111/febs.15178 [doi]
PST - ppublish
SO  - FEBS J. 2020 Jul;287(14):3065-3087. doi: 10.1111/febs.15178. Epub 2019 Dec 29.