p38MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects

Figures & data

Figure 1 Basic mechanism of p38MAPK pathway. The P38MAPK signaling pathway involves three key kinases: MAPKKK (beige box), MAPKK (blue box), and MAPK (orange box). P38MAPK signaling pathway can be affected by extracellular stimuli (red box) and then enter the nucleus to active transcription factors (green box).

Figure 2 Pathophysiology of OA related to p38MAPK. Aggrecan and collagen (purple box) are major components of cartilage. They are able to decomposed by a disintegrin-like and metalloproteinase with the thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMP) (red box) respectively. P38MAPK can induce expressions of MMP. IL-β and TNF-α (blue box) are always at a high level in cartilage of OA Patients. P38MAPK is also involved in this process.

Table 1 Factors Affecting p38MAPK and Progression of OA

Authors (Year)	Samples	Factors	Pathway(via)	Findings
Liao et al (2020)^Citation12	30C57bl/6 Mice	Advanced oxidation protein products (AOPPs)	p38MAPK, NADPH oxidase4-dependent,	↑TNF-α, IL-1β
Shan et al (2019)^Citation13	Normal Human Cartilage	Angiopoietin-like 2 (ANGPTL2)	p38MAPK, NF-κB (integrin α5β1)	↑IL-1β, IL-6 ↓ECM,
Ma et al (2019)^Citation14	Human Bone Marrow Mesenchymal Stem Cells (BMSCs)	TGF-β1	p38MAPK, ERK, JNK, Smad	↑SOX9, Collagen II, Aggrecan, GAG
Han et al (2020)^Citation50	OA patients’ Knee Cartilage	Kruppel like factors 11 (KLF11)	p38MAPK	↓oxidative stress levels, apoptosis levels, activity of ERS-related pathways
Wang et al (2017)^Citation91	Dawley rats, weighing 300–400 g (5 females and 5 males)	Pyruvate dehydrogenase kinase isoform 2 (PDK2)	P38MAPK, ERK, JNK	↑mesenchymal stem cells (MSCs)
Lei et al (2019)^Citation51	Normal Human Cartilage	LncRNA small nucleolar RNA host gene 1 (SNHG1)	p38MAPK, NF-κB (miR-16-5p)	↓NO, PGE2, IL-6, TNF-α, i-NOS, COX-2, MMPs, ADAMTs
Kang et al (2016)^Citation58	Young (2-week-old) and old (2-year-old) New Zealand White rabbits	Cyclosporine A (CsA) and tacrolimus (FK506)	p38MAPK	↓Senescence of articular chondrocytes
Benabdoune et al (2016)^Citation92	OA patients’ Knee Cartilage	Resolvin D1	p38MAPK, JNK, NF-κB (IL-1β)	↑Bcl2, AKT, GSH. ↓lactate dehydrogenase release
Zheng et al (2020)^Citation93	Adult SD rats	CTRP9	p38MAPK, NF-κB	↑IL-1β, IL-6 ↓MMPs

Table 2 The Natural Products and Traditional Chinese Medicine Extracts of p38MAPK

Authors (Years)	Samples	Extracts	Regulate	Pathways
Ren et al (2018)^Citation79	ATDC5 cells	Piperine	miR-127, MyD88	NF-κB, p38MAPK
Fan et al (2019)^Citation80	ATDC5 cells	Astragalus polysaccharide (APS)	miR-92a, KLF4 axis	NF-κB, p38MAPK
Jin et al (2018)^Citation81	ATDC5 cells	Resveratrol (RSV)	miR-146b	NF-κB, p38MAPK
Li et al (2019)^Citation82	ATDC5 cells	Tetramethylpyrazine (TMP)	MyD88	NF-κB, p38MAPK
Feng et al (2020)^Citation83	OA patients’ Cartilage	Salvianolic acid A (SAA)	↑Collagen II, Aggrecan. ↓MMP1, MMP13, ADAMTS-5	NF-κB, p38MAPK
Li et al (2021)^Citation84	KOA model mice	Wang-Bi Tablet (WBT)	↑glycosaminoglycans ↓IL-6	NF-κB, p38MAPK

Table 3 The Other Inhibitors of p38MAPK

Authors (Years)	Names	Research Field	Subject
Noguchi et al (2020)^Citation86	11R-p38I110	Islet	Porcine
Damjanov et al (2009)^Citation88	VX-702	RA	RA patients
Wagner et al (2015)^Citation87	VX-702	Platelet	Platelet
Ito et al (2008)^Citation94	P38IH	Pancreas	Canine
Bagley et al (2016)^Citation95	RO3201195	Werner syndrome	Werner syndrome cells

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