PMID- 34590154
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 24
IP  - 6
DP  - 2021 Dec
TI  - MAPK inhibitors protect against early‑stage osteoarthritis by activating 
      autophagy.
LID - 829 [pii]
LID - 10.3892/mmr.2021.12469 [doi]
AB  - Osteoarthritis (OA) is a chronic, age‑related osteoarthropathy that causes a 
      considerable decline in quality of life, as well as economic losses due to its 
      high incidence and poor prognosis. Mitogen‑activated protein kinases (MAPKs) 
      regulate multiple cellular processes, including proliferation, differentiation 
      and apoptosis, in certain diseases, such as cancer, diabetes and Alzheimer's 
      disease. The present study aimed to investigate the regulatory role of the MAPK 
      signaling pathway in early‑stage OA. A rabbit model of early‑stage OA was induced 
      by treatment with the enzyme papain. U0126 [an extracellular signal‑regulated 
      kinase (ERK) inhibitor], SP600125 [a Jun NH2‑terminal kinase (JNK) inhibitor] and 
      SB203580 (a p38 inhibitor) were administered to the rabbits via intra‑articular 
      injection. The severity of OA was assessed by histological examination using H&E, 
      toluidine blue and safranin‑O/fast green staining, as well by analyzing the 
      glycosaminoglycan (GAG) content and determining the OA Research Society 
      International (OARSI) score. Western blotting was used to detect the protein 
      expression levels of matrix metalloproteinase‑3 (MMP3), ERK, phosphorylated 
      (p)‑ERK, p38, p‑p38, JNK, p‑JNK, Beclin1, UNC‑51‑like kinase 1 (ULK1) and 
      microtubule‑associated protein 1 light chain 3 (LC3)II/I. U0126, SP600125 or 
      SB203580 treatment significantly decreased the OARSI scores and significantly 
      increased the GAG levels in the cartilaginous tissues of OA model rabbits. These 
      results indicated that the MAPK inhibitors reduced the severity of OA‑induced 
      injury at the early stage. Western blotting results demonstrated that MAPK 
      inhibition significantly decreased the protein expression levels of MMP3 in OA 
      cartilage. The protective effect of MAPK inhibitors in OA was mediated via the 
      activation of autophagy, as demonstrated by the increased protein expression 
      levels of LC3II/I, ULK1 and Beclin1. Overall, the data indicated that MAPK 
      inhibitors may exert a protective effect against OA by restoring compromised 
      autophagy. Furthermore, the present study suggested that MAPK inhibitors may 
      represent a potential pharmacological strategy for treating OA in the future.
FAU - Lan, Chun-Na
AU  - Lan CN
AD  - Department of Rehabilitation, The Second Xiangya Hospital of Central South 
      University, Changsha, Hunan 410011, P.R. China.
FAU - Cai, Wei-Jun
AU  - Cai WJ
AD  - Department of Histology and Embryology, School of Basic Medicine, Central South 
      University, Changsha, Hunan 410013, P.R. China.
FAU - Shi, Jie
AU  - Shi J
AD  - Department of General Surgery, The Third Xiangya Hospital of Central South 
      University, Changsha, Hunan 410013, P.R. China.
FAU - Yi, Zhong-Jie
AU  - Yi ZJ
AD  - Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central 
      South University, Changsha, Hunan 410011, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20210930
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Anthracenes)
RN  - 0 (Butadienes)
RN  - 0 (Imidazoles)
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (U 0126)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Animals
MH  - Anthracenes/pharmacology
MH  - Autophagy/*drug effects
MH  - Butadienes
MH  - Disease Models, Animal
MH  - Imidazoles/pharmacology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Nitriles
MH  - Osteoarthritis/*drug therapy/*metabolism/pathology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyridines/pharmacology
MH  - Rabbits
MH  - Severity of Illness Index
PMC - PMC8503737
OTO - NOTNLM
OT  - ERK
OT  - JNK
OT  - MAPKs
OT  - MMP3
OT  - autophagy
OT  - osteoarthritis
COIS- The authors declare that they have no competing interests.
EDAT- 2021/10/01 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/09/28
CRDT- 2021/09/30 07:25
PHST- 2020/12/04 00:00 [received]
PHST- 2021/09/01 00:00 [accepted]
PHST- 2021/09/30 07:25 [entrez]
PHST- 2021/10/01 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/09/28 00:00 [pmc-release]
AID - 829 [pii]
AID - MMR-0-0-12469 [pii]
AID - 10.3892/mmr.2021.12469 [doi]
PST - ppublish
SO  - Mol Med Rep. 2021 Dec;24(6):829. doi: 10.3892/mmr.2021.12469. Epub 2021 Sep 30.