The Effect of Cyclic Pressure On Integrin Beta 1 Hippo Yap Signaling Pathway
The Effect of Cyclic Pressure On Integrin Beta 1 Hippo Yap Signaling Pathway
The Effect of Cyclic Pressure On Integrin Beta 1 Hippo Yap Signaling Pathway
HSOA Journal of
Alternative, Complementary & Integrative Medicine
Research Article
The Effect of Cyclic Pressure Conclusion: The manipulation of regulating tendons could delay
the degeneration of chondrocytes and that mechanical stimulation to
on Integrin β 1-Hippo/YAP chondrocytes was partly mediated by ITG-β1 involved in the classi-
cal Hippo/YAP signaling pathway, and there were other unknown sig-
naling pathways involved in the regulation of YAP protein by ITG-β1.
Signaling Pathway Keywords: Cyclic Pressure; Integrin β1; Hippo/Yap Pathway; Knee
Osteoarthritis; Regulating Tendon Manipulation
Xia Li1, Hongkai Zhang1, Zhanying Tang1*, Jing Xiao1, Jia Wen
Cui2, Dan Liu1, Zhijun Hu1, Lixi Chu2 and Shuai Zhang3
1
Department of Rehabilitative Medicine, Longhua Hospital Affiliated to Shang-
Introduction
hai University of Traditional Chinese Medicine, Xuhui, Shanghai, China
Knee Osteoarthritis (KOA) is a common disease caused by mul-
2
Faculty of Rehabilitation Medicine, Shanghai University of Traditional Chi- tiple factors, which seriously affects the health and quality of life of
nese Medicine, Shanghai, China elderly people [1,2]. With the increasing age, the incidence of the
3
Department of Orthopedics and Traumatology, Shanghai Pudong New Dis- disease is on the rise [3,4]. Epidemiological research results show
trict Hospital of Traditional Chinese Medicine, Shanghai, China that the incidence rate of KOA reaches 50% for the middle-aged and
elderly over 60 years old, while the incidence rate of KOA rises to
80% for those over 75 years old [5]. At present, the prevention and
Abstract
rehabilitation of KOA has become a worldwide problem [6,7]. The
Objectives: To clarify the mechanism of traditional Chinese medi- pathogenesis of KOA is caused by the imbalance of synthesis and
cine treatment of Knee Osteoarthritis (KOA), this study would further degradation of chondrocytes, extracellular matrix and subchondral
study the changes of integrin and Hippo/YAP signaling pathways.
due to the interaction and joint action of two factors of knee joint
Methods: The study of differential expression proteomics of chon- mechanics and biology. Many basic and clinical studies have been
drocytes after mechanical stimulation intervention was to explore to carried out. Integrin, as a transmembrane protein, is mainly located on
clarify the mechanism of KOA. the cartilage cell membrane [8,9]. Its main function is to mediate the
Results: The proteomic analysis identified 1697 proteins, and mechanical stimulation signals from outside the cell to enter the cell,
there were 333 up-regulated and 194 down-regulated differentially and then regulate the signal pathway changes in the cell, thus reg-
expressed proteins in pressure group and normal group. The pro- ulating the metabolism of cartilage cells. Therefore, integrin-related
tein level in hippo signaling pathway implied that ITG-β1, CYR61, signal pathways have been widely concerned as a hot topic in many
MOB1and Smad2 were differentially expressed proteins in the three researches.
groups. The expression of ITG-β1 mRNA and protein in chondro-
cytes and cartilage was significantly up-regulated after cyclic stress Traditional Chinese medicine manipulation is one of the basic
or the intervention of reinforcement manipulation. Compared with methods for the treatment of osteoarthritis, and has its unique fea-
the model group, the expression of YAP1 protein, mRNA and TEAD tures in the treatment of knee osteoarthritis [10,11]. It is based on
mRNA were significantly increased in the pressure group, and the the principles of relaxing muscles and tendons, dredging collaterals,
expression of YAP1 protein, mRNA and TEAD mRNA were signifi-
promoting blood circulation, relieving pain, releasing adhesion and
cantly increased in the manipulation group. Logistic linear regression
analysis in chondrocytes and cartilage showed that there was a sig-
smoothing joints, promoting blood circulation around joints, improv-
nificant correlation between ITG-β1 and MST1 gene expression, and ing cell metabolism, promoting chondrocyte proliferation and inhibit-
a significant correlation between ITG-β1 and YAP gene and protein ing cell apoptosis, thus achieving the aims of relieving inflammation,
expression. loosening adhesion and improving joint function. The previous re-
search preliminarily confirmed that the Flexcell system was applied
*Corresponding author: Zhanying Tang, Department of Rehabilitative Medicine,
to simulate the different degrees of periodic pressure, and it could
Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Med- promote or inhibit chondrocyte proliferation through the regulation
icine, Xuhui, Shanghai, China, Tel: +86 02151322222, Fax: +86 02151322459; of integrin [12]. The hippo signaling pathway was one of the highly
E-mail: [email protected] conserved signal pathways in mammals [13,14]. Transcription factor
TAZ/YAP played an important biological function in regulating cell
Citation: Li X, Zhang H, Tang Z, Xiao J, Cui JW, et al. (2023) The Effect of Cyclic
Pressure on Integrin β 1-Hippo/YAP Signaling Pathway. J Altern Complement growth, proliferation and apoptosis [15,16]. Current research has pre-
Integr Med 9: 429. liminarily confirmed that the hippo signaling pathway not only played
a role in maintaining the internal environment stability and tumor de-
Received: November 29, 2023; Accepted: December 11, 2023; Published: De- velopment, but also played an important role in signal transduction of
cember 18, 2023
mechanical stimulation.
Copyright: © 2023 Li X, et al. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted Chondrocyte degeneration is the basis of the pathogenesis of
use, distribution, and reproduction in any medium, provided the original author KOA, and the mechanism of mechanical factors in the degeneration
and source are credited. of chondrocytes has been a hot topic. To clarify the mechanism of
Citation: Li X, Zhang H, Tang Z, Xiao J, Cui JW, et al. (2023) The Effect of Cyclic Pressure on Integrin β 1-Hippo/YAP Signaling Pathway. J Altern Complement Integr
Med 9: 429.
• Page 2 of 6 •
traditional Chinese medicine treatment of KOA, based on the study of was used for RT-qPCR amplification. The primers used for PCR are
differential expression proteomics of chondrocytes after mechanical shown in table 1. The cycling conditions were 95℃ for 5 min, fol-
stimulation intervention, this study would further study the chang- lowed by 35 cycles of 90℃ for 10 s, 50 ℃ for 35 s, and 72 ℃ for
es of integrin and Hippo/YAP signaling pathways closely related to 30 s, and 72 ℃ for 5 min. The RT-qPCR analysis was performed
mechanical stimulation, and the changes of these signaling pathways with the Light Cycler 480 RT-qPCR System (Roche, Basel, Switzer-
after intervention by rational manipulation. land). Fold-changes in gene expression were estimated using the CT
comparative method normalizing GAPDH CT values and relative to
Materials and Methods control samples as follows: ΔCt=Ct (assayed samples)-Ct(β-actin);
Samples ΔΔCt=ΔCt-ΔCt control; fold difference = 2-(ΔΔCT).
The chondrocytes derived from the two-week-old male SD rats Genes Forward (5’–3’) Reverse (5’–3’)
were randomly divided into normal group, model group and pressure GCCTTCCACTACAATATGAG- ATCAGCTGTCCTGGCCA-
MST1
group. The chondrocytes in normal group were cultured under normal CAGC CAGTG
pressure and environment. The chondrocytes in model group were YAP CCACCCCTGCTGCTCAACAT
TTGGGAGAGCATGG-
cultured in the medium with TNF-α reagent to simulate the OA in- CCTTCC
flammatory environment under the condition of normal pressure. The TAED GCCCTGTGGGAGGAGGAAAA
CACGAGATTTCCTTCTGG-
chondrocytes in pressure group were stimulated by TNF-α to simulate CAAG
172 KPa, and the cyclic compressive stress of 2Hz was given for 3 GAPDH AATGGATTTGGACGCATTGGT TTGCACTGGTACGTGTTGAT
days continuously for 60 min/d. Table 1: Primers used for quantitative RT-PCR.
Proteomics
Western Blot Analysis
Total protein was subjected to proteomic analysis. Tryptic peptides
from each sample (200 ug) were injected with an EASY-nLC1000 The total protein was extracted with lysis buffer, and 50 mg pro-
HPLC (Thermo Fisher Scientific), which was equipped with an tein was resolved on a 5% sodium dodecyl sulfate polyacrylamide
EASY column SC200 150 um *100 mm (RP-C18), trapped at 300 gel. The fractionated proteins were electrophoretically transferred
μL/min on a Thermo column. The mass spectrometer was operated
to an immobilon polyvinylidene difluoride membrane and probed
in a data-dependent mode. Full-scan MS spectra were obtained in an
with antibodies of GAPDH, YAP1 and ITGβ1 (ProteinTech Group,
quadrupole Orbitrap mass spectrometer (Q Exactive) at a mass reso-
lution of 70,000 (mass range 300-1800 m/z). For label-free analysis, Chicago, IL, USA).
the ten most abundant tandem mass spectrum peaks were obtained in Statistical analysis
a linear ion trap by peptide cleavage. The isolation width was 2 m/z.
Proteins were identified using Maxquant software (1.5.5.1). The Raw SPSS 18.0 was used for statistical analysis. All data were ex-
file was imported and used to search in the UniProt KB /Swiss-Prot pressed as means ± SD. Statistical analysis was performed using
database (36088 sequences, version 2018.06.14). one-way analysis of variance, and followed by the Wilcoxon test for
Proteomics data analysis comparison of two groups. Statistical significance was considered at
P < 0.05.
For database searches, the peptide mass tolerances were set to 20
ppm. The following parameters were used: trypsin as enzyme speci- Results
ficity; maximum two missed cleavage permitted; variable modifica- Protein analysis of chondrocytes
tions: Cys carbamidomethylation, Oxidation (M); precursor ion mass
tolerance of 20 ppm. Peptides with a false positive rate ≤ 0.01 were The proteomic analysis identified 7874 peptides and 1697 pro-
selected. Proteins that met the following criteria were differentially teins. Among all the identified proteins, there were 81 up-regulated
expressed proteins: mean change in protein ≥ 1.5 or ≤ 0.667 (Stu- and 128 down-regulated differentially expressed proteins in the model
dent’s t-test, p < 0.05). GO and KEGG pathway enrichment analysis group and the normal group, and there were 333 up-regulated and
of differentially expressed proteins were performed. 194 down-regulated differentially expressed proteins in the pressure
group and the normal group. After that, the function and pathway an-
TUNEL and ELISA assays
notation of differentially expressed proteins were performed (Figure
The chondrocytes were detected by using a TUNEL kit (Boster, 1). In the model group and the normal group, the differentially ex-
Wuhan, China) according to the manufacturer’s instructions. The pressed proteins were enriched in RNA processing, mRNA metabolic
chondrocytes were collected, and Bcl-2 and Bax was quantified by process, mRNA processing, RNA splicing, mRNA splicing, via spli-
using a commercially available ELISA kit (eBioscience) according to ceosome, intracellular part, membrane-bounded organelle, intracel-
the manufacturer’s instructions. lular, organelle, intracellular organelle part, RNA binding, poly(A)
RNA binding, organic cyclic compound binding, binding and hetero-
RT-PCR cyclic compound binding (Figure 1A). Meanwhile, the differentially
Total RNA of chondrocytes was isolated using Trizol (Invitro- expressed proteins were enriched in those pathways, such as Spliceo-
gen, Carlsbad, USA), and was reverse-transcribed into cDNA using some, Valine, leucine and isoleucine degradation, Proteasome, Fatty
a Super RT cDNA kit. The SYBR green Realtime PCR Master Mix acid degradation and Adherens junction (Figure 1B).
J Altern Complement Integr Med ISSN: 2470-7562, Open Access Journal Volume 9 • Issue 10 • 100429
DOI: 10.24966/ACIM-7562/100429
Citation: Li X, Zhang H, Tang Z, Xiao J, Cui JW, et al. (2023) The Effect of Cyclic Pressure on Integrin β 1-Hippo/YAP Signaling Pathway. J Altern Complement Integr
Med 9: 429.
• Page 3 of 6 •
In the pressure group and the normal group, the differentially ex-
pressed proteins were enriched in organic substance metabolic pro-
cess, cellular metabolic process, cellular component organization or
biogenesis, macromolecular complex subunit organization, metabolic
process, intracellular part, cytoplasm, intracellular, intracellular or-
ganelle, cytoplasmic part, poly(A) RNA binding, RNA binding, pro-
tein binding, binding and nucleotide binding (Figure 1C). Meanwhile,
the differentially expressed proteins were enriched in those pathways,
such as spliceosome, carbon metabolism, citrate cycle (TCA cycle),
pyruvate metabolism, RNA transport, proteasome, Glycolysis / Glu-
coneogenesis, valine, leucine and isoleucine degradation, fatty acid
degradation, biosynthesis of amino acids, protein processing in en-
doplasmic reticulum, fatty acid metabolism, mRNA surveillance
pathway, propanoate metabolism, regulation of actin cytoskeleton,
tryptophan metabolism, metabolic pathways, endocytosis, glyoxylate
and dicarboxylate metabolism, pentose phosphate pathway, bacterial
invasion of epithelial cells, 2-Oxocarboxylic acid metabolism, oocyte
meiosis, legionellosis, adherens junction, hippo signaling pathway,
insulin signaling pathway, synaptic vesicle cycle, long-term potentia-
tion and central carbon metabolism in cancer (Figure 1D).
• Page 4 of 6 •
Pressure group 4 8.56 ± 0.05**## SPF grade SD rats were randomly divided into normal group,
Table 2: Comparison of apoptosis rate of chondrocytes in each group.
model group and manipulation group with 10 rats in each group. KOA
model was established by medial collateral ligament resection com-
Note: * represented p < 0.05 compared with the normal group; ** repre- bined with partial patellar ligament resection in rats. After 4 weeks of
sented p < 0.01 compared with the normal group; # represented p < 0.05
compared with the model group; ## represented p < 0.01 compared with
modeling, the rats in the manipulation group were treated with ma-
the model group. nipulation intervention for 7 minutes each time, once every other day,
for 6 weeks. No intervention in normal group and model group. HE
staining results showed that in the normal group, the cartilage of knee
Groups N Bcl-2 (ng/ml) Bax (ng/ml) joint was smooth, the chondrocytes were spindle-shaped, horizontal
Normal group 4 5.86 ± 0.24 1.67 ± 0.03 arrangement, and the structure of tidal line was clear and complete
Model group 4 2.13 ± 0.17** 3.92 ± 0.16** (Figure 4). In the model group, there was moderate wear on the ar-
Pressure group 4 4.15 ± 0.21**## 2.41 ± 0.09**##
ticular cartilage surface and the loss of chondrocytes was obvious in
the model group. In manipulation group, the cartilage surface of knee
Table 3: Apoptosis-related protein (Bcl-2 and Bax) level of chondrocytes
in each group. joint was slightly worn, the morphology of chondrocytes was close
to normal, and the phenomenon of chondrocyte clustering was less.
Note: * represented p < 0.05 compared with the normal group; ** repre- The Mankin score of the model group was significantly higher than
sented p < 0.01 compared with the normal group; # represented p < 0.05
compared with the model group; ## represented p < 0.01 compared with that of the normal group (P < 0.01) (Table 4). After manual therapy,
the model group. the Mankin score of the manipulation group was significantly lower
than that of the model group (P < 0.01), but it was still higher than
that of the normal group (P < 0.01) (Table 4). There was a significant
difference between the model group and the normal group (P < 0.01),
and the apoptosis rate of chondrocytes in the manipulation group was
significantly different from that in the model group (P < 0.05) (Table
5).
J Altern Complement Integr Med ISSN: 2470-7562, Open Access Journal Volume 9 • Issue 10 • 100429
DOI: 10.24966/ACIM-7562/100429
Citation: Li X, Zhang H, Tang Z, Xiao J, Cui JW, et al. (2023) The Effect of Cyclic Pressure on Integrin β 1-Hippo/YAP Signaling Pathway. J Altern Complement Integr
Med 9: 429.
• Page 5 of 6 •
Funding Statement
Figure 5: The mRNAs and proteins in Hippo/YAP pathway of knee joint • This study is supported by 1.Scientific research plan of Shanghai
of rats in each group. A: the ITGB1 mRNA expression in normal group, Municipal Health Commission, No: 202040240
model group and manipulation group; B: the MST1 mRNA expression in
normal group, model group and manipulation group; C: the YAP1 mRNA • Shanghai Jinshan expert workstation construction project, No.:
expression in normal group, model group and manipulation group; D: the jszjz2021017y
TAED mRNA expression in normal group, model group and manipulation
group; E: the YAP protein expression in normal group, model group and • Three year action plan no (ZY (2021-2023) - 0201-01) for Shang-
manipulation group; F: the ITGB1 protein expression in normal group,
model group and manipulation group. * represented p < 0.05 compared hai to further accelerate the inheritance, innovation and develop-
with the normal group; ** represented p < 0.01 compared with the normal ment of traditional Chinese medicine
group; # represented p < 0.05 compared with the model group; ## repre-
sented p < 0.01 compared with the model group. • Original exploration project of Shanghai Science and Technology
Commission, No: 20zr147340
J Altern Complement Integr Med ISSN: 2470-7562, Open Access Journal Volume 9 • Issue 10 • 100429
DOI: 10.24966/ACIM-7562/100429
Citation: Li X, Zhang H, Tang Z, Xiao J, Cui JW, et al. (2023) The Effect of Cyclic Pressure on Integrin β 1-Hippo/YAP Signaling Pathway. J Altern Complement Integr
Med 9: 429.
• Page 6 of 6 •
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