Mechanism of NLRP3 inflammasome intervention for synovitis in knee osteoarthritis: A review of TCM intervention

Abstract

Objective: This paper briefly reviews the structure and function of NLRP3 inflammasomes, signaling pathway, relationship with synovitis in KOA, and intervention of traditional Chinese medicine (TCM) in NLRP3 inflammasomes as a means to improve its therapeutic potential and clinical application.
Method: Literatures about NLRP3 inflammasomes and synovitis in KOA were reviewed to analyze and discuss.
Result: NLRP3 inflammasome can activate NF-κB mediated signal transduction, which in turn causes the expression of proinflammatory cytokines, initiates the innate immune response, and triggers synovitis in KOA. The TCM monomer/active ingredient, decoction, external ointment, and acupuncture regulating NLRP3 inflammasomes are helpful to alleviate synovitis in KOA.
Conclusion: The NLRP3 inflammasome plays a significant role in the pathogenesis of synovitis in KOA, TCM intervention targeting the NLRP3 inflammasome can be a novel approach and therapeutic direction for the treatment of synovitis in KOA.

Full text

Mechanism of
NLRP3 inflammasome
intervention for synovitis in knee
osteoarthritis: A review of TCM
intervention
Xianfu Han
1†
, Demin Lin
1†
, Weiwei Huang
1
, Dingpeng Li
2
,
Ning Li
1
,
3
* and Xingwen Xie
3
*
1
Clinical Medical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu,
China,
2
Department of Orthopedics, The Second People’s Hospital of Gansu Province, Lanzhou, Gansu,
China,
3
Department of Orthopedics, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou,
Gansu, China
Objective: This paper briefly reviews the structure and function of
NLRP3 inflammasomes, signaling pathway, relationship with synovitis in KOA,
and intervention of traditional Chinese medicine (TCM) in NLRP3 inflammasomes
as a means to improve its therapeutic potential and clinical application.
Method: Literatures about NLRP3 inflammasomes and synovitis in KOA were
reviewed to analyze and discuss.
Result: NLRP3 inflammasome can activate NF-κB mediated signal transduction,
which in turn causes the expression of proinflammatory cytokines, initiates the
innate immune response, and triggers synovitis in KOA. The TCM monomer/active
ingredient, decoction, external ointment, and acupuncture regulating NLRP3
inflammasomes are helpful to alleviate synovitis in KOA.
Conclusion: The NLRP3 inflammasome plays a significant role in the pathogenesis
of synovitis in KOA, TCM intervention targeting the NLRP3 inflammasome can be a
novel approach and therapeutic direction for the treatment of synovitis in KOA.
KEYWORDS
NLRP3 inflammasome, synovitis, knee osteoarthritis, traditional Chinese medicine, review
Introduction
KOA is a degenerative joint condition that is brought on by a number of reasons and
frequently coexists with synovitis (Mathiessen and Conaghan, 2017). Although the
pathophysiology of synovitis in KOA is not entirely clear, related research has revealed
that the innate immune response plays a crucial part in the disease’s pathogenesis (Wang
et al., 2018). An essential PRRs in the innate immune system, the NLRP3 inflammasome
can activate the NF-κB signaling pathway by identifying pathogen-related molecular
patterns (PAMPs) and damage-related molecular patterns (DAMPs), inducing an innate
immune response, activating or accelerating the transmission of downstream signaling
molecules, and leading to synovitis (Huang et al., 2022). In order to provide a theoretical
foundation and point of reference for the diagnosis and treatment of synovitis in KOA,
this article reviews and analyzes historical data regarding the role of the
OPEN ACCESS
EDITED BY
Bing Shu,
Shanghai University of Traditional
Chinese Medicine, China
REVIEWED BY
Nanxing Yi,
Hunan University of Chinese Medicine,
China
Hongting Jin,
Zhejiang Chinese Medical University,
China
*CORRESPONDENCE
Ning Li,
1316022420@qq.com
Xingwen Xie,
827975272@qq.com
†
These authors have contributed equally
to this work and share first authorship
SPECIALTY SECTION
This article was submitted to
Human and Medical Genomics,
a section of the journal
Frontiers in Genetics
RECEIVED 05 February 2023
ACCEPTED 07 March 2023
PUBLISHED 29 March 2023
CITATION
Han X, Lin D, Huang W, Li D, Li N and Xie X
(2023), Mechanism of
NLRP3 inflammasome intervention for
synovitis in knee osteoarthritis: A review
of TCM intervention.
Front. Genet. 14:1159167.
doi: 10.3389/fgene.2023.1159167
COPYRIGHT
© 2023 Han, Lin, Huang, Li, Li and Xie.
This is an open-access article distributed
under the terms of the Creative
Commons Attribution License (CC BY).
The use, distribution or reproduction in
other forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
Frontiers in Genetics frontiersin.org01
TYPE Review
PUBLISHED 29 March 2023
DOI 10.3389/fgene.2023.1159167

NLRP3 inflammasome for synovitis in KOA as well as the
research status of TCM interventions on the
NLRP3 inflammasome.
The structure and function of
NLRP3 inflammasome
The inflammasome is a multiple proteins complex that exists
in the cytoplasm of cells. It was first proposed by Martinon et al.
(2002).Itismainlyformedduringtheactivationofcaspase-1by
nucleotide-binding oligomerization domain (NOD) like
receptors in PRRs. NOD-like receptors play an important role
in innate immunity, among which NLRP3 inflammasome is the
most deeply studied (Zhang et al., 2021a). NLRP3 consists of an
amino-terminal pyridine domain (PYD), a central NACHT
domain, and a carboxyl-terminal leucine-rich repeat (LRR)
(Gaul et al., 2021). Studies have shown that the NACHT
domain has ATP binding activity to promote the
oligomerization of NLRP3, LRR and NACHT domains form a
mutual inhibitory effect, and the PYD domain allows NLRP3 to
interact with other inflammasome proteins (Hafner-Bratkovič
et al., 2018). NLRP3 exists in the cytoplasm and participates in
innate immunity as PRRs. It is activated by recognizing PAMPs
and DAMPs (Zhao et al., 2022a). NLRP3 inflammasome consists
of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR)
and pyrin domain containing receptor 3), ASC (apoptosis-
associated speck-like protein containing a caspase recruitment
domain), and Pro-caspase-1 (Zahid et al., 2019). NLRP3 is
considered to be the site of the sensing activation signals. ASC
is the adaptor protein of NLRP3 inflammasome, which connects
NLRP3 and Pro-caspase-1. The phosphorylation of ASC
promotes the activation of the inflammasome. Pro-caspase-
1 has no catalytic activity, but it can be activated into the
effector protein Caspase-1 of the NLRP3 inflammasome by its
shearing. Caspase-1 can transform inactive Pro-IL-1βand Pro-
IL-18 into mature IL-1βand IL-18 (Huang et al., 2021). It has
been found that NLRP3 is easily activated in dendritic cells,
macrophages, and neutrophils (Zhao et al., 2022b). The
NLRP3 inflammasome pathway belongs to the classical
inflammasome pyroptosis pathway (Caspase-1 mediated). In
addition, there are non-classical inflammasome pyroptosis
pathways (Caspase-4, Caspase-5, Caspase-11 mediated) and
apoptotic protein Caspase-3 mediated pyroptosis pathway
(Moretti et al., 2022;Fu et al., 2021;Zhang et al., 2021b). The
role of NLRP3 inflammasome for synovitis in KOA is a hot topic
in recent years, many studies have shown that
NLRP3 inflammasome is a potential mechanism of synovitis
in KOA, but it needs to be further studied.
NLRP3 inflammasome signaling
pathway
NLRP3 inflammasome mainly senses stimulation signals in cells
and can be activated by a variety of internal and external factors,
such as PAMPs and DAMPs, including lipopolysaccharide (LPS),
amyloid β, cholesterol crystals, monosodium urate crystals (MSU),
adenosine triphosphate (ATP), fatty acids, and hyaluronic acid.
Some bacteria and fungi can also activate NLRP3 as PAMPs. In
addition to the above factors, crystal or granular structures such as
silica, asbestos, and alum can also activate NLRP3 and cause
inflammatory cascade amplification (Kelley et al., 2019;Swanson
et al., 2019;McGettrick et al., 2020).
It has been found that there are two signal models for
NLRP3 inflammasome activation (Figure 1): the first step is
initiated at the transcriptional level, in which Toll-like
receptors recognize PAMPs or DAMPs to activate NF-κB-
mediated signal pathway, which increases the production of
pro-IL-1β, pro-IL-18 and NLRP3 proteins. The second step is
the activation signal, which initiates NLRP3 oligomerization and
causes NLRP3, ASC, and Pro-caspase-1 to form inflammasomes.
Subsequently, Pro-caspase-1 is self-sheared and activated to
Caspase-1 p10 and Caspase-1 p20. After Caspase-1 is
activated, pro-IL-1βand pro-IL-18 can be sheared into mature
IL-1βand IL-18 (Li et al., 2021;Mu et al., 2022;Zhang et al., 2022;
Zhang et al., 2018;Pei et al., 2022). Then released to the outside of
thecell,andmoreinflammatory cells (HMGB1, leukotrienes,
prostaglandins, etc.) were collected, which led to the cascade of
inflammation.
The molecular mechanisms of NLRP3 inflammasome
activation mainly include potassium outflow, calcium
signaling, lysosomal destruction, mitochondrial dysfunction,
and Golgi. Potassium ion outflow causes a decrease in
intracellular potassium levels under the stimulation of ATP,
pore-forming toxins, crystals, particles, etc. Then directly
bindsandactivatesNLRP3undertheactionofNIMA-
associated kinase 7 (Nek7) (Sun et al., 2022). Plant-derived
dietary lectins are internalized, then escaped from the
lysosome and are transported to the endoplasmic reticulum.
Endoplasmic reticulum-loaded lectins trigger calcium ion
release and mitochondrial damage. It was found that blocking
the flow of calcium ions can inhibit NLRP3 inflammasome
components and activation. Promoting calcium ion release can
aggravate mitochondrial damage, and mediated mitochondrial
damage can cause NLRP3 inflammasome activation. And
promoting the release of calcium ions can aggravate the injury
of mitochondria, and calcium ion-mediated mitochondrial
damage could cause the activation of NLRP3 inflammasome
(Murakami et al., 2012). Lysosomal damage releases cathepsin
B directly binds to the NLRP3 inflammasome and promotes the
activation of the NLRP3 inflammasome (Ma et al., 2022). The
release of mitochondrial ROS (mt ROS) and mitochondrial DNA
(mt DNA) caused by mitochondrial dysfunction is another
important cause of NLRP3 inflammasome activation. For
example, after the increase of ROS caused by NLRP3 agonist,
the redox stress mediated by thioredoxin interacting protein
(TXNIP) can activate the NLRP3 inflammasome (Luo et al.,
2022).ItwasfoundthattheGolgiapparatusisinvolvedin
NLRP3 inflammasome activation through protein kinase D
signaling on mitochondria-associated endoplasmic reticulum
membranes (Zhang et al., 2017). In addition, some infectious
microorganisms have been shown to activate the
NLRP3 inflammasome (Giraud et al., 2019). In conclusion,
NLRP3 inflammasome is a key host immune defense
mechanism for the body to face PAMPs or DAMPs. With the
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deepening of research, NLRP3 inflammasome will provide more
ideas for the treatment of many diseases.
The role of NLRP3 inflammasome for
synovitis in KOA
The expression of NLRP3 inflammasome in
KOA synovium
Synovitis is one of the important causes of cartilage degeneration
(Oka et al., 2021). IL-1βinvolved in cartilage degradation may be
produced by synovial cells rather than chondrocytes (Wang et al.,
2021). Synovitis is relatively more studied in rheumatoid arthritis
(RA). It has been found that NLRP3 inflammasome is highly
activated in the synovium of RA patients and collagen-induced
arthritis mice. The activation of NLRP3 inflammasome mainly
occurs in infiltrating monocytes/macrophages in the synovium.
The NLRP3 inhibitor MCC950 can significantly inhibit the
activation of NLRP3 inflammasome in the synovium and reduce
the production of IL-1β(Guo et al., 2018). Clavijo-Cornejo et al.
found that the protein expression of NLRP3 in the synovium of
KOA patients increased 5.4-fold with respect to normal patients
(Clavijo-Cornejo et al., 2016). Sakalyte et al. found that
NLRP3 inflammasome existed in synovial fibroblast cell of KOA
patients and showed high expression (Sakalyte et al., 2022). The
activation of NLRP3 inflammasome promotes synovitis, which
participates in the whole process of KOA and promotes the
progress of KOA.
NLRP3 inflammasome mediates synovitis
in KOA
ThecourseofsynovitisinKOAofteninvolvesthe
participation of immune cells, and innate immunity is an
important barrier for the human body to prevent the invasion
of pathogens. PRRs can recognize and perceive DAMPs or
PAMPs, and combine with them to form ligand polymer,
which can cause and promote synovitis in KOA after
activating the innate immune response (Leung et al., 2015).
NLRP3 inflammasome, as a PRRs, can activate the NF-κBsignal
pathway after combining with DAMPs and PAMPs expressed or
secreted in the synovium, causing the expression of pro-
inflammatory cytokines and inflammatory mediators, then
leading to synovitis. Which can promote synovial cell
proliferation, and aggravate synovitis (Zhang et al., 2019a). In
KOA synovial macrophages, NLRP3 inflammasomes are
induced and released into the synovial fluid and surrounding
tissues under the action of different DAMPs. Which increased
the expression levels of IL-1βand IL-18 in a series of
inflammatory reactions involving synovial macrophages and
chondrocytes (An et al., 2020). Eventually, this led to
synovitis and cartilage degeneration.
Chen et al. found that the Nrf2/HO-1 signal in the synovium of
KOA patients and model rats may be an important way to activate the
NLRP3 inflammasome. Oxidative stress induced by ROS may be the
main reason for the activation of NLRP3 inflammasome and the
subsequent release of downstream pro-inflammatory factors in the
development of KOA (Chen et al., 2019). The activation of
FIGURE 1
Mechanism of NLRP3 activation requires two signals. The first priming signal is provided through the interaction of PAMPS/DAMPs with TLRs. This
initiates NF-κB signaling, which upregulates the production of pro-IL-1β, pro-IL-18, and inactive NLRP3 protein. The second step is an activation signal
which causes NLRP3, ASC, and Pro-caspase-1 to come together. Pro-caspase-1 is then converted into active caspase-1, along with NLRP3 and ASC
forms the NLRP3 inflammasome complex. Active caspase-1 cleaves pro-IL-1βand pro-IL-18 causing their activation, which converts into IL-1βand
IL-18, subsequent release to extracellular. The molecular mechanisms of NLRP3 inflammasome activation mainly include potassium outflow, calcium
signaling, lysosomal destruction, mitochondrial dysfunction, and Golgi.
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NLRP3 inflammasome can induce the secretion of proinflammatory
cytokines IL-1βand IL-18, leading to the aggravation of downstream
inflammatory response and accelerating the occurrence of synovitis in
KOA. In addition to ROS, the ectopic deposition of hydroxyapatite
(HA) crystals in joints are related to the pathogenesis of synovitis in
KOA. HA crystals induce macrophages to secrete IL-1 and IL-18 in an
NLRP3 inflammasome-dependent manner. In addition, calcium
crystals in the synovial fluid of KOA patients showed
NLRP3 inflammasome stimulating activity in vitro (Jin et al.,
2011). It was found that the level of uric acid was positively
correlated with the expression of IL-18 and IL-1βin synovial fluid
of KOA patients, while uric acid could activate NLRP3 inflammasome
and increase the expression of IL-18 and IL-1β, then led to the
aggravation of synovitis. This indicates that there was a close
relationship between NLRP3, uric acid, and proinflammatory
cytokines (Aibibula et al., 2016). HA crystal, MSU crystal,
calcium pyrophosphate, and calcium phosphate also were
inflammasome activators (Busso and So, 2012). Zhao et al. found
that NLRP3 inflammasome in the synovium of KOA patients was
involved in synovial fibroblast cell inflammation and pyroptosis.
Inhibition of NLRP3 inflammasome can significantly reduce
the expression of apoptosis-related cytokines (Zhao et al., 2018).
Xiao et al. found that NLRP3 inflammasome mediated synovial
fibroblast cell pyroptosis can enhance the secretion of high
mobility group protein B1 (HMGB1), and HMGB1 has a pro-
inflammatory effect and aggravates synovitis (Xiao et al., 2021).
Zhang et al. found that hypoxia in the synovium of KOA model
rats led to an increase in hypoxia-inducible factor 1α(HIF-1α),
resulting in an increase in the expression of NLRP3, Caspase-1and
GSDMD. Thereby aggravating synovitis and fibrosis in KOA (Zhang
et al., 2019b).
TCM interventions on the
NLRP3 inflammasome for synovitis
in KOA
The intervention effect of TCM on the NLRP3 inflammasome
for synovitis in KOA via TCM monomer/active ingredient,
Decoction, External ointment, and Acupuncture (Table 1).
TCM monomer/active ingredient
Casticin
Casticin is a compound purified from the TCM Viticis
Fructus. In rats KOA model induced by monoiodoacetic acid
(MIA) and the inflammation of primary FLS stimulated by
TABLE 1 Traditional Chinese Medicine against synovitis in KOA.
Species Drugs/methods Research
object
Mechanism
TCM Monomer/Active
ingredient
Casticin Rats/FLS Inhibits the activation of HIF-1α/NLRP3 inflammasome
Agnuside Rats/FLS Inhibits the activation of HIF-1α/NLRP3 inflammasome
Chrysin Rats Inhibits the activation of NLRP3 inflammasome
Vanillic Acid Rats/FLS Decreases the expression of caspase-1, ASC, and NLRP3 and also reduce the
levels of IL-1βand IL-18
Nodakenin Mice/Chondrocytes Regulates the mitochondrial Drp1/ROS/NLRP3 axis
Isochlorogenic acid A Rats Decreases the activation of NLRP3 inflammasome and NF-κB
phosphorylation expression
Xanthotoxol Rats Inhibits the infiltration of inflammatory factors and downregulates the
activity of the NF-κB signal pathway by inhibiting the activation of
NLRP3 inflammasome
Andrographolide Mice/Chondrocytes Regulates the circ_Rapgef1/miR-383–3p/NLRP3 signaling axis
Decoction Xibining Rats Inhibits the activation of HIF-1α/NLRP3 inflammasome
Du Huo Ji Sheng Tang Human/Rat Suppresses NLRP3/NF-κBinflammatory signals
External Ointment Layers Adjusting External Application Rats Suppresses the expression of NLRP3, ASC, Caspase-1 protein and mRNA in
the synovium
“Sanse Powder”Essential Oils
Nanoemulsion
SD rats/FLS Inhibits the ERS/TXNIP/NLRP3 signaling axis
“Sanse Powder”Volatile Oil FLS Inhibits the activation of NLRP3 inflammasome
Acupuncture electroacupuncture SD rats Inhibits the NLRP3 inflammasome signaling pathway and reducing
pyroptosis
electroacupuncture Guinea pigs Suppresses the activation of NLRP3 inflammasome
moxibustion combined with ultrashort
wave
Human Suppresses NLRP3 inflammasome signaling pathway
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lipopolysaccharide (LPS), Casticin can improve hypoxia,
inflammation of synovium and synovium fibrosis in rats. In
addition, Casticin can inhibit the activation of
NLRP3 inflammasome in rats KOA model and FLS, indicating
that Casticin alleviates MIA-induced synovitis in KOA by
inhibiting the activation of HIF-1α/NLRP3 inflammasome (Li
et al., 2020a).
Agnuside
Agnuside is a non-toxic natural small molecule isolated from
the extract of Vitex negundo. In MIA-induced rats KOA model
and LPS-induced FLS inflammation model, it was found that
Agnuside could effectively alleviate local hypoxia in the
synovium, reduce the mRNA and protein levels of HIF-1α,
caspase-1, ASC, and NLRP3. Meantime downregulate the
expression of NLRP3 inflammasome downstream factors IL-1β
and IL-18, also fibrosis markers TGF-β,TIMP1,andVEGF.Itis
indicated that Agnuside reduces synovitis and fibrosis in
experimental KOA by inhibiting the activation of HIF-1α/
NLRP3 inflammasome (Zhang et al., 2021c).
Chrysin
Chrysin is a natural flavonoid found in Scutellaria baicalensis
Georgi. In the rats KOA model induced by MIA, Chrysin can not
only reduce synovitis but also reduce the secretion of pain-related
factors, and increase the mechanical pain threshold and cold pain
threshold of rat. Chrysin alleviates synovitis by inhibiting
NLRP3 inflammasome activation and IL-1βexpression. It is
suggested that Chrysin can reduce synovitis in KOA and
improve pain behavior in rats, which may be related to the
ability to inhibit the activation of NLRP3 inflammasome (Liao
et al., 2020).
Vanillic acid
Vanillic Acid is a monomer from Chinese herbal medicine. It
was found that Vanillic acid decreased the expression of caspase-
1, ASC, and NLRP3 in rats KOA model both in vivo and vitro and
also reduced the levels of IL-1βand IL-18, which reduced
synovium fibrosis and alleviated pain-related behaviors in rats
KOA model. The expression of pain mediators CGRP, NGF, and
TrkA in FLS was downregulated. It shows that Vanillic Acid
reduces synovitis and pain-related behaviors in rats KOA model
(Ma et al., 2021).
Nodakenin
Nodakenin is the main coumarin active ingredient in Angelicae
Pubescentis Radix. It was found that Nodakenin could increase
trabecular bone score in subchondral bone, reduce the level of serum
inflammatory factors and alleviate synovitis in mice KOA model
after Nodakenin intervention. In vitro, it was found that Nodakenin
inhibited the phosphorylation of kinesin-related protein 1 (Drp1)
and ROS production in chondrocytes stimulated by LPS through
DRP1-dependent mitochondrial division. In addition, Nodakenin
inhibited the mRNA levels of inflammatory factors (COX 2, IL-1β,
and TNF-α), NLRP3 inflammasome, and MMP13 in activated
chondrocytes. It indicated that Nodakenin alleviates cartilage
degradation and synovitis in KOA by regulating the
mitochondrial Drp1/ROS/NLRP3 axis (Yi et al., 2022).
Isochlorogenic acid A
Isochlorogenic acid A, as a natural product of quinic acid and
caffeic acid by esterification and condensation, mostly exists in
Lonicera japonica, Celastrus angulatus, L. japonica, and other
plants. Isochlorogenic acid A can significantly reduce the
expression of NLRP3, caspase-1, NF-κB p65, p-NF-κB p65,
p-IκB, and RANKL in the synovium of collagen-induced arthritis
rats, downregulate plasma IL-1β, IL-6, TNF-ɑ, CRP, IFN-γand IL-
18, and reduce the swelling of rats toes. Isochlorogenic acid A has a
good anti-inflammatory effect on collagen-induced arthritis, and its
anti-inflammatory activity may be related to decreasing the
activation of NLRP3 inflammasome and NF-κB phosphorylation
expression (Liu et al., 2019).
Xanthotoxol
Xanthotoxol is a coumarin compound extracted from Chinese
herbal medicine’s common cnidium fruit. In the rats KOA model
established by papain, xanthotoxol can significantly reduce joint
swelling, synovial hyperemia, and synoviocyte proliferation,
meantime reduce synovium inflammatory cell infiltration and
vascular proliferation.
It can significantly reduce the levels of IL-6, IL-1β,andTNF-α
in synovial fluid, and reduce the content of NLRP3 protein and
NF-κB phosphorylated protein in synovium. Xanthotoxol
inhibits the infiltration of inflammatory factors and
downregulates the activity of the NF-κB signal pathway by
inhibiting the activation of NLRP3 inflammasome. Thereby
inhibiting the expression of inflammatory factors, relieving
synovitis in KOA, and exerting a protective effect on
osteoarthritis (Zhuang et al., 2019).
Andrographolide
Andrographolide is the main active ingredient of the natural
plant Andrographis paniculata. Andrographolide can reduce the
infiltration of inflammatory cells in synovium, and inhibit the
inflammatory response in mice KOA model established by
anterior cruciate ligament transection (ACLT). It can inhibit
the proliferation, apoptosis, and inflammation of chondrocytes
induced by LPS stimulation. Andrographolide inhibits the
progression of osteoarthritis by regulating the circ_Rapgef1/
miR-383–3p/NLRP3 signaling axis (Yan et al., 2022).
Decoction of TCM
Xibining
Xibining (patent number: CN201010514325) is a TCM
compound developed by ProfessorPeiminWangaimingat
KOA clinical treatment with the therapeutical principle of
warming channels and activating blood circulation. Medicine
composition and dosage: Radix Aconiti Carmichael 15 g,
Processed cibotium barometz 15 g, human placenta 10 g,
Cornus officinalis 1 5g, Wilson cinnamon bark 15 g, Morinda
officinalis 10 g, Jobstears seed 10 g, Tuber fleece flower root 10 g,
Medicinal cyathia root 10 g, Radix glycyrrhiza 5 g. In the rats
KOA model established by sodium iodoacetate, after xibining
treatment, the infiltration of inflammatory cells in the synovium
of rats KOA decreased. The infiltration of inflammatory cells,
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mRNA, and protein expression of HIF-1α,NLRP3,ASC,
GSDMD, and Caspase-1 in synovium were decreased.
Meantime the levels of IL-1βand IL-18 in synovium
decreased. Thereby Xibining can effectively improve the
hypoxia condition of the synovium in KOA, reduce the
expression of HIF-1α, reduce the activation of the
NLRP3 inflammasome, and reduce synovitis in KOA (Zhang
et al., 2020).
Du Huo Ji Sheng Tang
Du Huo Ji Sheng Tang (DHJST) is a TCM formula, which is a
classic prescription for the treatment of KOA. The levels of serum
IL-1β, IL-6, IL-10, TNF-α,NLRP3,ASC,Caspase-1,p-NF-κB-
P65, and p-IκBa were decreased in KOA patients after DHJST
treatment. In the rats KOA model established by Papain Enzyme,
after DHJST intervention, the swelling volume of the right hind
foot of the rats was significantly reduced, and the levels of IL-1β,
IL-6, and TNF-αin synovial fluid of the knee joint were
downregulated, meantime the expression of NLRP3, ASC,
Caspase-1, p-NF-κB-P65, and p-IκBa in the synovium of the
knee joint was decreased, and the pathological changes such as
synovitis and cartilage degeneration of the knee joint were
alleviated. DHJST alleviated KOA by suppressing NLRP3/NF-
κBinflammatory signals in rats (Chen et al., 2020).
External ointment of TCM
Layers Adjusting External Application
Layers Adjusting External Application (Patent No:
ZL200820185241.8) is a TCM ointment for external use,
which is composed of Chinese medicines for warming
meridians and activating blood circulation. Layers Adjusting
External Application can improve the Krenn score of synovitis
in rats KOA model, downregulate the expression of serum IL-1β
and TNF-α, downregulate the expression of NLRP3, ASC,
Caspase-1 protein and mRNA in the synovium, meantime
downregulate levels of MMP-1 and MMP-13 in cartilage.
Layers Adjusting External Application may inhibit synovitis in
KOA by down-regulating the expression of NLRP3 and Caspase-
1, reducing the level of cartilage MMPs, and playing a role in
protecting cartilage (Li et al., 2020b).
“Sanse Powder”
“Sanse Powder”is the core component of Layers Adjusting
External Application (Patent No: ZL200820185241.8). It is a
hospital preparation of the Department of Orthopedics and
Traumatology of the Affiliated Hospital of Nanjing University
of Traditional Chinese Medicine. It is one of the representative
prescriptions for warming meridians and activating blood
circulation. In rats synovitis in KOA model and FLS
stimulated by LPS, “Sanse Powder”Essential Oils
Nanoemulsion can inhibite ERS/TXNIP/NLRP3 signaling axis
to regulate the excessive production of IL-1βand IL-18 (Liu et al.,
2021). In KOA inflammatory cell model established by LPS,
“Sanse Powder”Volatile Oil can downregulate the protein and
mRNA expression of NLRP3, caspase-1, and ASC, meantime
reduce the levels of IL-1βand IL-18 in cell supernatant. It may
playaroleinimprovingsynovitisinKOAbyinhibitingthe
activation of NLRP3 inflammasome in FLS and reducing the
downstream inflammatory cascade (Liao et al., 2021).
Acupuncture
In the KOA model of SD rats established by Papain Enzyme,
after electroacupuncture stimulation of “Neixiyan”(EX-LE4)
and “Dubi”(ST35), the pathological score of synovium, serum
IL-1β, and IL-18 levels, synovium NLRP3, ASC, Caspase-1, IL-
1β,IL-18mRNAandproteinexpression levels were decreased,
meantime the expression of GSDMD mRNA and GSDMD-N
protein was also decreased. Electroacupuncture can reduce the
inflammatory response of knee joint synovium in rats, which
may be related to inhibiting the NLRP3 inflammasome signaling
pathway and reducing pyroptosis (Yu et al., 2022). In the guinea
pigs KOA model, after electroacupuncture treatment, the
mechanical withdrawal threshold of guinea pigs was
downregulated, the articular cartilage structure was improved,
and the fibrosis on the cartilage surface was reduced.
Electroacupuncture can inhibit the activation of the
NLRP3 inflammasome, and inhibit the protein expression
levels of caspase-1 and IL-1βin cartilage tissue.
Electroacupuncture alleviates KOA pain by suppressing the
activation of NLRP3 inflammasome (Wang et al., 2021).
Wang et al. observed the effect of moxibustion combined
with ultrashort wave on elderly patients with KOA. The
results showed that the total effective rate of the observation
group was 90.48%. After treatment, the VAS and WOMAC
scores of the observation group decreased, and the Lysholm
knee joint scores increased. The serum IL-1β,TNF-α,SOD,
MDA, miR-155, and NLRP3 were all lower than those before
treatment. The results show that moxibustion combined with an
ultrashort wave can effectively improve the knee joint pain and
function of elderly KOA patients, reduce oxidative stress
response, and the potential mechanism may be through
Suppressing NLRP3 inflammasome signaling pathway (Wang
et al., 2022b).
Conclusion
The NLRP3 inflammasome plays a significant role in the
pathogenesis of synovitis in KOA, and innate immunity is activated
during the pathogenesis of this condition. The NF-κB signaling
pathway, pro-inflammatory factor production, inflammatory
mediator secretion, synovitis in KOA, and synovial cell proliferation
can all be brought on by the activation of the NLRP3 inflammasome.
The pathophysiology of synovitis in KOA can be further understood by
analysis of the role of the NLRP3 inflammasome. Targeting the
NLRP3 inflammasome can be a novel approach and therapeutic
direction for the treatment of synovitis in KOA. The research
conclusions are mostly from animal or in vitro experiments. The
effectiveness and safety of clinical applications are not completely
clear. Further depth research is needed.
Frontiers in Genetics frontiersin.org06
Han et al. 10.3389/fgene.2023.1159167

Author contributions
All authors listed have made a substantial, direct, and intellectual
contribution to the work and approved it for publication.
Funding
This study was funded by National Natural Science Foundation
of China (No. 82060873).
Acknowledgments
Special thanks go to other Department of orthopedics colleagues
for their insightful comments on this study and DL for English
language editing.
Conflict of interest
The authors declare that the research was conducted
in the absence of any commercial or financial
relationships that could be construed as a potential conflict of
interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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