Abstract
- Osteoarthritis, resulting from joint decline, leads to various symptoms including joint pain, stiffness, tenderness, and local inflammation. These symptoms may be caused by the remodeling of the five structural phenotypes: inflammatory, subchondral bone, meniscal cartilage, atrophic, and hypertrophic phenotypes. Studies have shown that acupuncture can inhibit cartilage degradation by regulating extracellular matrix-degradation and enzyme synthesis. Notably, the efficacy of acupuncture treatment in osteoarthritis may be attributed to regulated inflammation and apoptosis of chondrocytes, as well as endogenous opioid production, and activation of the endocannabinoid systems (in the central and peripheral nervous systems), to contribute towards cartilage protection and joint pain relief. This review provides a current summary of the mechanisms of action of acupuncture in osteoarthritis, indicating that acupuncture, a therapy with fewer side effects than conventional medications, may be an effective treatment strategy for the management of osteoarthritis.
-
Keywords: acupuncture, apoptosis, inflammation, osteoarthritis, pain
Visual abstract
Introduction
- Osteoarthritis is one of the most prevalent musculoskeletal diseases, causing a deterioration in joint function and thereby affecting overall quality of life. In the United States, an estimated 10% of men and 13% of women aged over 60 years exhibit symptoms indicative of osteoarthritis [1]. Furthermore, the annual medical expenses linked to osteoarthritis surpass $60 billion and could escalate to over $185.5 billion [2]. Clinical manifestations of osteoarthritis encompass joint pain, stiffness, tenderness, and localized inflammation [3]. Notably, for instance, excessive physical activity may contribute to the persistent joint pain in the development of osteoarthritis. [4]. The joint pain associated with osteoarthritis involves mechanisms of pain within the peripheral nervous system (PNS) and central nervous system (CNS), alongside structural alterations in the joint [5]. Treatment of osteoarthritis frequently involves the use of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. These medications pose a substantial risk of adverse effects, encompassing digestive, and cardiovascular complications [6].
- Acupuncture, a practice dating back thousands of years in East Asia, has been utilized to address chronic musculoskeletal disorders, including osteoarthritis and rheumatoid arthritis [7–10]. It has been reported not only to ameliorate structural and functional changes in cartilage (by reducing apoptosis and inflammation) but also alleviates heightened pain sensitivity (through modulated central sensitization) [11–14]. However, the mechanisms of this phenomenon remain elusive. This review aimed to elucidate the underlying mechanisms by summarizing recent preclinical studies on the effects of acupuncture in the treatment of osteoarthritis.
Results and Discussion
-
1. Pathophysiology of osteoarthritis
- Osteoarthritis is a degenerative joint disease characterized by pain, limited range of motion, and joint dysfunction, primarily attributed to the articular cartilage degradation and subchondral bone sclerosis [15]. Articular cartilage, comprising over 70% water and various organic extracellular matrix (ECM) components such as Type II collagen, aggrecan, and other proteoglycans, plays a crucial role in joint function [16]. Chondrocytes, the resident cells of cartilage, respond to external mechanical and inflammatory stimuli primarily through ECM component receptors. This response promotes cartilage degradation by upregulating the activity of aggrecanase and collagenase [17]. Matrix metallopeptidase (MMP)-13 (collagenase-3), a member of the MMP family of neutral endopeptidases [18], not only efficiently degrades fibrillar collagens like Type I and II collagen but also targets Type II collagen and aggrecan [19]. The disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family consists of 19 members, with ADAMTS5 being a representative aggrecanase subtype [20,21]. The mouse knockout model of ADAMTS5 reduces proteoglycan damage caused by the destabilization of the medial meniscus (DMM), highlighting the crucial role of ADAMTS5 and proteoglycans in maintaining cartilage integrity [21].
- Osteoarthritis induces the remodeling of five structural phenotypes: inflammatory, subchondral bone, meniscus-cartilage, atrophic, and hypertrophic phenotypes [22]. The subchondral bone remodeling is characterized by the development of the blood vessels containing osteoblasts and sensory nerves. The growth of these blood vessels facilitates molecular biological communication between the bone and cartilage. Continuous stress between the bone and cartilage triggers the secretion of inflammatory substances such as cytokines, chemokines, and adipokines, by chondrocytes. This secretion promotes the inflammatory process by recruiting macrophages and fibroblasts into the synovial fluid. Consequently, this cycle leads to chondrocyte death and progressive cartilage loss [17].
-
2. Pathophysiology of osteoarthritis pain
- The cartilage, being an aneural structure, does not directly induce pain. However, its surrounding structures including the subchondral bone, synovium, ligaments, periosteum, and joint capsule, which are richly innervated and contain nerve endings, produce nociceptive stimuli in osteoarthritis [23,24]? Noxious stimuli are responsible for pain transfer sensory signals to the dorsal root ganglia (DRG) via nerve endings of primary sensory afferent neurons containing nociceptors. Subsequently, sensory signals from the DRG are conveyed to the brainstem through the dorsal horn of the spinal cord. In investigating sensory signal transmission to the DRG in osteoarthritis pain, Ca2+ imaging revealed increased activation of DRG neurons in response to noxious stimuli in both DMM and anterior cruciate ligament transection-induced osteoarthritis mice models [25,26].
- Inflammation can perpetuate pain by inducing synaptic plasticity [27,28]. Toll-like receptors (TLRs), crucial in the inflammatory response, prompt the synthesis of inflammatory cytokines and chemokines, thereby modulating tissue homeostasis [29]. Notably, in TLR4 null or TLR2 null mice, while DMM surgery induces cartilage damage, it reduces knee hyperalgesia [30,31]. Thus, in osteoarthritis, neural activation triggered by inflammation associated with TLRs within the CNS may underlie persistent pain.
-
3. Effect of acupuncture on cartilage degradation in osteoarthritis
- Acupuncture, a treatment originating in East Asia, has been reported to alleviate pain and enhance joint function in patients with osteoarthritis [32–34]. In addition to manual acupuncture which stimulates through rotation, electroacupuncture which stimulates using electricity, and fire needling acupuncture which stimulates using heat, are also used to alleviate the symptoms of osteoarthritis [14,35,36]. Preclinical studies have shown that different types of acupuncture inhibit the elevation of ECM degradative enzymes such as ADAMTS5, MMP-13, and MMP-9, thus hindering the degradation of Type II collagen, aggrecan, and proteoglycans, consequently protecting against joint degeneration [13,37,38]. The joint-protective effect of acupuncture is believed to be mediated by various physiological mechanisms, including inflammation, apoptosis, and epigenetics (Figure 1 and Table 1 [13,14,36–42]).
- In the monosodium iodoacetate (MIA) rat model, electroacupuncture treatment was administered in early, middle, and late stages of osteoarthritis after MIA induction. For mechanical allodynia assessed by the von Frey test, while all stages were effectively treated with electroacupuncture and relieved pain, only early-stage treatment significantly protected against cartilage degradation [39]. Additionally, epigenetic modifications in the CNS are increasingly recognized as important in osteoarthritis and chronic pain treatment. Acupuncture has been reported to suppress chronic pain by mediating epigenetic modifications [43–45]. These modifications, such as deoxyribonucleic acid (DNA) methylation and histone modification, regulate gene expression without altering the DNA base sequence [46]. In osteoarthritic chondrocytes, MMP-3, -9, and -13 promoters are hypomethylated, leading to increased gene expression [47]. Recently, in a study by Luobin et al [40], it was reported that electroacupuncture inhibited an increase in activity of DNA methyltransferase family members and restored decreased levels of histone H3 expression in cartilage and synovial tissue of an anterior cruciate ligament transection rat model.
- In a study by Tan et al [14], it was indicated that manual acupuncture suppressed joint inflammation and joint bone destruction. This was detected using positron emission tomography imaging analysis in the MIA model of osteoarthritis. Macrophages are highly phenotypically plastic immune cells which play a pivotal role in inflammatory regulation by adapting to the local microenvironment under physiological and pathological conditions [48]. Activated macrophages undergo differentiation into 2 distinct phenotypes: M1 and M2 [50]. M1 macrophages, exhibit a pro-inflammatory phenotype, secrete cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Conversely, M2 macrophages, display an anti-inflammatory phenotype and release cytokines such as transforming growth factor-β and IL-10 [50,51]. TLRs in macrophages initiate the NF-κB signaling pathway, leading to the release of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by translocating NF-κB into the nucleus [52]. Several studies have shown that electroacupuncture inhibits NF-κB activation and the production of inflammatory cytokines [13,37,40]. In addition, in a study by Wei et al [36], it was reported that fire needling acupuncture decreases the number of M1 macrophages and increases the number of M2 macrophages in the MIA-induced osteoarthritis model [36].
- Additionally, the Ras-Raf-mitogen-activated protein kinase (MAPK) 1/2-extracellular signal-regulated kinase 1/2 signaling pathway modulates TNF-α-mediated immune responses, contributing to cartilage degradation. Activation of the nucleotide oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) induces inflammatory responses by regulating cytoplasmic signaling complexes known as inflammasomes, which activate NF-κB and MAPK signaling pathways. Inflammasomes, comprising multiprotein oligomers including apoptosis-associated speck-like proteins containing a caspase recruitment domain, NLRs, and the downstream effector protein caspase-1, produce inflammatory cytokines including IL-1β, IL-18, and gasdermin D, eliciting an inflammatory response leading to pyroptotic cell death [53–55]. Recent studies have shown that electroacupuncture not only inhibits the Ras-Raf-MAPK 1/2-extracellular signal-regulated kinase 1/2 signaling pathway activated by TNF-α in chondrocytes but also reduces the NLRP3 inflammasome-mediated pyroptosis through downregulating the expression of apoptosis-associated speck-like protein and caspase-1 in the MIA model [37,38].
- Apoptosis, a physiological process of cell death, and plays a crucial role in development and tissue homeostasis [57]. It serves as a pivotal mechanism for chondrocyte death within cartilage. The B-cell lymphoma 2 (Bcl-2) family of proteins plays a pivotal role in modulating apoptosis, exhibiting either anti- or pro-apoptotic activities by regulating mitochondrial membrane permeabilization [58]. Bcl-2, an anti-apoptotic protein, mitigates apoptosis by inhibiting heightened mitochondrial permeability [59]. Conversely, Bcl-2-associated-X operates as a pro-apoptotic member, counteracting the function of Bcl-2 [41]. Acting as downstream effectors of the Bcl-2 family of proteins, caspase-3 and -9 serve as executors and activators of apoptosis, respectively [57]. In a study by Lin et al [41], it was reported that electroacupuncture not only upregulated the expression of Bcl-2 but also downregulated the expression of Bcl-2-associated-X, caspase-3, and -9 in chondrocyte apoptosis following sodium nitroprusside treatment. In addition, silent mating-type information regulation 2 homolog 1 (SIRT1) plays a critical role in cellular processes, including apoptosis and inflammation [59]. In a study by Liu et al [13], it was indicated that manual acupuncture enhanced the expression of SIRT1 in the articular cartilage of an anterior cruciate ligament transection-induced osteoarthritis model, with its effect being attenuated in short hairpin SIRT1 (shSIRT1) mice [13].
- Norepinephrine, a neurotransmitter secreted from the brainstem, plays a pivotal role in regulating various physiological functions such as arousal, cognition, and attention through its interaction with α1-, α2-, and β2-adrenergic receptors [60,61]. These adrenergic receptors are distributed in synovial cells, and β2-adrenoceptor signaling within synovial tissues is closely associated with the inflammatory response of fibroblast-like synoviocytes [62,63]. Moreover, norepinephrine inhibits the release of TNF-α and IL-8 mediated by β2-adrenergic receptors in synovial macrophages derived from patients with osteoarthritis and rheumatoid arthritis [64]. A recent study has indicated that electroacupuncture enhanced the production of norepinephrine in the locus coeruleus and rostral ventrolateral medulla as well as in the synovium, but chemical sympathetic denervation inhibited the anti-inflammatory effect of acupuncture on the synovium. Subsequently, it was reported that electroacupuncture modulated the activity of β2-adrenergic receptors on synovial macrophages in synovial tissue through sympathetically delivered norepinephrine [42].
-
4. Effect of acupuncture on the pain modulation in osteoarthritis
- Acupuncture is known for its low incidence of adverse effects and has a strong capacity to reduce pain. Clinical and preclinical studies have reported its effectiveness in relieving pain associated with osteoarthritis [10–12,65–67]. In osteoarthritis, electroacupuncture appears to contribute to pain modulation through various physiological systems such as the endogenous opioid, endocannabinoid, and serotonergic systems (Figure 2 and Table 2 [11,12,67–70]). The endogenous opioid system plays a pivotal role in the analgesic effects of acupuncture, functioning as a complex neuronal system in the CNS and PNS. This system exerts analgesic effects on nociceptive signals received by μ-, δ-, and κ-opioid receptors distributed in the dorsal horn of the spinal cord [71–73]. In the collagenase-induced arthritis model, electroacupuncture treatment increased the reduced thermal pain threshold, and the analgesic effect was inhibited by μ- and δ-opioid receptor antagonists. This result suggests that the analgesic effect of electroacupuncture in osteoarthritis is mediated by μ- and δ-opioid receptors [12].
- The endocannabinoid system plays an important role in the modulation of pain and inflammation in the CNS and PNS via cannabinoid (CB) receptors exist in a subtype which exist in 2 subtypes known as CB1 and CB2 receptors [74,75]. CB1 receptors interact with inhibitory gamma-aminobutyric acid (GABA)ergic neurons in the periaqueductal gray matter, contributing to pain suppression by activating the descending pain-inhibitory pathway [76]. In the MIA model, electroacupuncture reduced mechanical allodynia and heat hyperalgesia by increasing the concentration of 2-arachidonoylglycerol, a member of the endocannabinoid family, and activating CB1 receptors and GABAergic neurons in the periaqueductal gray matter [67]. While CB2 receptors are primarily expressed in immune cells, evidence suggests their distribution in chondrocytes, synovial cells, and fibroblasts [77–79]. Electroacupuncture was reported, by Yuan et al [68], to upregulate CB2 receptor expression in menisci of wild-type mice and downregulated the expression of IL-1β through CB2 receptors [68].
- Serotonin (or 5-HT) within the CNS serves as an essential neurotransmitter and neuromodulator, regulating various physiological functions, including pain sensitivity, emotions, and cognition [80]. Given its role in modulating synaptic transmission and plasticity within the brain and spinal cord, 5-HT receptors have garnered attention as potential therapeutic targets for chronic pain management [81–84]. The analgesic effects of electroacupuncture have been reported, by Seo et al [69], to be impeded by systemic 5-HT subtypes, 5-HT1 and 5-HT3 receptor antagonists, underscoring the involvement of the 5-HT neuromodulatory system in acupuncture-induced analgesia [69]. Furthermore, electroacupuncture exerts an analgesic effect through 5-HT2A/2C receptors in the nuclear raphe and 5-HT2A receptors in the spinal cord [11,70]. Additionally, interactions between the 5-HT neuromodulatory system and the endocannabinoid system have been observed in the brain, and regulate diverse behavioral functions including pain sensitivity, emotions, and cognition [85–87]. Interestingly, in a study by Yuan et al [67], it was reported that electroacupuncture elevates 5-HT levels in the medulla of wild-type mice, whereas no increase was observed in GABA-CB1 knockout mice [67]. These results suggest that CB1 receptors and GABAergic neurons are likely to be involved in the release of 5-HT.
Conclusion
- Acupuncture has been reported not only to ameliorate structural and functional changes in cartilage (by reducing apoptosis and inflammation) but also alleviate heightened pain sensitivity (through modulated central sensitization). The mechanisms of this phenomenon are clearer but need to be substantiated.
- This study reviewed the mechanisms underlying the modulatory effects of different types of acupuncture on cartilage degradation and joint pain in osteoarthritis. Given the complex therapeutic challenge posed by osteoarthritis, understanding the role of various mechanisms including inflammation, apoptosis, epigenetics, and pain modulation in osteoarthritis pathophysiology was paramount. Preclinical studies of electro, manual, and fire acupuncture, appear to modulate multiple aspects of cartilage protection, and electroacupuncture appears to have pain management qualities. The studies in this review have provided evidence for potential clinical efficacy in the treatment of osteoarthritis with acupuncture.
- The molecular mechanisms driving the efficacy of types of acupuncture in improving cartilage protection and pain modulation within the CNS and PNS mostly involved electroacupuncture. Since the mechanisms of electroacupuncture, manual and fire acupuncture may be different, it is necessary to understand the mechanisms separately.
- Further research is imperative to determine the specific molecular and biological changes induced by different types of acupuncture in the treatment of osteoarthritis. Exploring the potential of acupuncture in conjunction with conventional treatments holds promise for a comprehensive management strategy for patients with osteoarthritis to ultimately enhance quality of life.
- In summary, this review article delineates the manifold mechanisms through which acupuncture appears to contribute to cartilage protection and pain management in osteoarthritis, thus, advocating for a holistic approach towards the scientific validation of traditional medicine.
Article information
-
Author Contributions
Conceptualization: JHJ. Visualization: JHJ, JH, and CSN. Writing original draft: JHJ. Writing - review and editing: JHJ and HJP.
-
Conflicts of Interest
The authors have no conflict of interest to declare.
-
Funding
This research was supported by grants from the National Research Foundation of Korea funded by the Korean government (grant no.: NRF-2020R1I1A1A01072607, NRF-2021R1A2C2006818, NRF-2022M3A9B6017813, RS-2024-00409969), and by an Undergraduate Research Program of the College of Korean Medicine, Kyung Hee University.
-
Ethical Statement
This research did not involve any human or animal experiments.
Data Availability
All relevant data are included in this manuscript.
Figure 1
Mechanisms of acupuncture’s impact on cartilage degradation in osteoarthritis. Acupuncture suppresses the degradation of ECM components by regulating inflammation, apoptosis, and epigenetic modifications caused by osteoarthritis. Furthermore, acupuncture may have anti-inflammatory effects on cartilage via sympathetic nerves by increasing the release of NE in the LC and RVLM. The red arrows pointing upward and downward indicate alterations following osteoarthritis. The blue sharp arrows indicate activation following acupuncture treatment. The blue blunt arrows indicate inhibition induced by acupuncture.
ADAMTS5 = disintegrin and metalloproteinase with thrombospondin motifs 5; Bax = Bcl-2 associated X; Bcl-2 = B-cell lymphoma 2; EA = electroacupuncture; ECM = extracellular matrix; FA = fire needling acupuncture; LC = locus coeruleus;
M1 = M1 phenotype macrophage; M2 = M2 phenotype macrophage; MA = manual acupuncture; MMP = matrix metallopeptidase; NE = norepinephrine; RVLM = rostral ventrolateral medulla.
Figure 2
Mechanisms of acupuncture’s effect on pain modulation in osteoarthritis. Acupuncture suppresses inflammation by regulating CB2 receptors for pain signals developed in the synovial tissue. It reduces the ascending pain pathway by activating opioid and serotonin receptors in the dorsal horn of the spinal cord. In addition, in the PAG and RVM, acupuncture enhances the descending pain pathway by increasing the release of serotonin, and the CB1 receptor activity of GABAergic neurons, which may ultimately reduce pain. The red arrows pointing up and down appear to be altered following osteoarthritis. The blue sharp arrows indicate enhancement by acupuncture. The blue blunt arrows indicate suppression by acupuncture.
CB = cannabinoid; EA = electroacupuncture; 5-HT = serotonin; NRM = nucleus raphe magnus; PAG = periaqueductal gray matter; RVM = rostral ventromedial medulla.
Table 1Acupuncture Protocols and Sham Controls in the Treatment of Osteoarthritis: A Focus on Cartilage Degradation
Author (y) |
Acupuncture type |
Acupoints |
Methods |
Tx sessions |
Sham control procedures |
Chen (2017) [38] |
EA |
EX-LE4, ST35 |
2 Hz, 2 mA, 15 min or 30 min |
Once daily for 3 d |
N/A |
Lin (2018) [41] |
EA |
N/A |
30 min or 60 min |
Once daily for 5 or 7 d |
N/A |
Ma (2018) [39] |
EA |
ST35, ST36 |
2/10 Hz, 1 mA, 30 min |
6 d/wk for 2 wks |
N/A |
Liu (2021) [13] |
MA |
ST35, ST36 |
2 rotations/1 sec, 1 min, remained still for 4 min |
6× |
N/A |
Tan (2022) [14] |
MA |
ST36 |
Manual rotation, 1 min every 5 min, total time 30 min |
6 d/wk for 3 wks |
Same insertion without MS |
Wei (2022) [36] |
FA |
EX-LE5, ST35, ST34, SP10 |
200 °C, 0.1 sec |
Once every other day for 2 wks |
N/A |
Chen (2023) [42] |
EA |
GB34, ST36 |
2/15 Hz, 1 mA, 30 min, |
3× |
N/A |
Luobin (2023) [40] |
EA |
EX-LE4, ST35 |
2/100 Hz, 30 min |
Once daily for 8 wks |
N/A |
Zhang (2022) [37] |
EA |
GB34 |
2/100 Hz, 0.1 mA, 15 min |
Once daily for 7 d |
N/A |
Table 2Acupuncture Protocols and Sham Controls in the Treatment of Osteoarthritis: A Focus on Pain Modulation
Author (y) |
Acupuncture modality |
Acupoints |
Frequency (Hz) |
Current (mA) |
Time (min) |
Tx sessions |
Sham control procedures |
Li (2011) [70] |
EA |
GB30, ST36 |
10 |
2 |
30 |
Once daily for 1–4 d |
N/A |
Seo (2013) [12] |
EA |
ST36 |
2 |
N/A |
30 |
Once daily for 7 d |
Abdominal nonacupoint |
Seo (2016) [69] |
EA |
ST36 |
2, 100 |
0.07 |
30 |
6 d/wk for 2 wks |
N/A |
Yuan (2018) [67] |
EA |
EX-LE4, ST35 |
2, 15, 100 |
1/0.1 |
30 |
Once every other day for 4 wks |
N/A |
Yuan (2018) [68] |
EA |
EX-LE4, ST35 |
2 |
1 |
30 |
Once every other day for 4 wks |
N/A |
Yuan (2022) [11] |
EA |
EX-LE4, ST35 |
2 |
1 |
30 |
Once every other day for 4 wks |
Same insertion without ES |
References
- [1] Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med 2010;26(3):355−69.ArticlePubMedPMC
- [2] Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum 2009;60(12):3546−53.ArticlePubMed
- [3] Jang S, Lee K, Ju JH. Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. Int J Mol Sci 2021;22(5):2619. ArticlePubMedPMC
- [4] Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther 2009;11(1):203. ArticlePubMedPMC
- [5] Perrot S. Osteoarthritis pain. Best Pract Res Clin Rheumatol 2015;29(1):90−7.ArticlePubMed
- [6] Juni P, Reichenbach S, Egger M. COX 2 inhibitors, traditional NSAIDs, and the heart. BMJ 2005;330(7504):1342−3.ArticlePubMedPMC
- [7] Zhang Y, Wang C. Acupuncture and chronic musculoskeletal pain. Curr Rheumatol Rep 2020;22(11):80. ArticlePubMedPMCPDF
- [8] Flynn DM. Chronic musculoskeletal pain: nonpharmacologic, noninvasive treatments. Am Fam Physician 2020;102(8):465−77.PubMed
- [9] Manyanga T, Froese M, Zarychanski R, Abou-Setta A, Friesen C, Tennenhouse M, et al. Pain management with acupuncture in osteoarthritis: a systematic review and meta-analysis. BMC Complement Altern Med 2014;14:312. ArticlePubMedPMCPDF
- [10] Corbett MS, Rice SJ, Madurasinghe V, Slack R, Fayter DA, Harden M, et al. Acupuncture and other physical treatments for the relief of pain due to osteoarthritis of the knee: network meta-analysis. Osteoarthritis Cartilage 2013;21(9):1290−8.ArticlePubMedPMC
- [11] Yuan XC, Wang YY, Tian LX, Yan XJ, Guo YX, Zhao YL, et al. Spinal 5-HT(2A) receptor is involved in electroacupuncture inhibition of chronic pain. Mol Pain 2022;18:17448069221087583. ArticlePubMedPMCPDF
- [12] Seo BK, Park DS, Baek YH. The analgesic effect of electroacupuncture on inflammatory pain in the rat model of collagenase-induced arthritis: mediation by opioidergic receptors. Rheumatol Int 2013;33(5):1177−83.ArticlePubMedPDF
- [13] Liu H, Zhang T, Liu M, Wang C, Yan J. Acupuncture delays cartilage degeneration through upregulating sirt1 expression in rats with osteoarthritis. Evid Based Complement Alternat Med 2021;2021:2470182. ArticlePubMedPMCPDF
- [14] Tan Q, Cai Z, Li J, Li J, Xiang H, Li B, et al. Imaging study on acupuncture inhibiting inflammation and bone destruction in knee osteoarthritis induced by monosodium iodoacetate in rat model. J Pain Res 2022;15:93−103.ArticlePubMedPMCPDF
- [15] van der Kraan PM. Osteoarthritis year 2012 in review: biology. Osteoarthritis Cartilage 2012;20(12):1447−50.ArticlePubMed
- [16] Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers 2016;2:16072. ArticlePubMedPDF
- [17] Houard X, Goldring MB, Berenbaum F. Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr Rheumatol Rep 2013;15(11):375. ArticlePubMedPMCPDF
- [18] Wu CW, Tchetina EV, Mwale F, Hasty K, Pidoux I, Reiner A, et al. Proteolysis involving matrix metalloproteinase 13 (collagenase-3) is required for chondrocyte differentiation that is associated with matrix mineralization. J Bone Miner Res 2002;17(4):639−51.ArticlePubMedPDF
- [19] Vonk LA, Doulabi BZ, Huang C, Helder MN, Everts V, Bank RA. Collagen-induced expression of collagenase-3 by primary chondrocytes is mediated by integrin α1 and discoidin domain receptor 2: a protein kinase C-dependent pathway. Rheumatology (Oxford) 2011;50(3):463−72.ArticlePubMed
- [20] Kelwick R, Desanlis I, Wheeler GN, Edwards DR, The ADAMTS. (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome Biol 2015;16(1):113. PubMedPMC
- [21] Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005;434(7033):644−8.ArticlePubMedPDF
- [22] Roemer FW, Jarraya M, Collins JE, Kwoh CK, Hayashi D, Hunter DJ, et al. Structural phenotypes of knee osteoarthritis: potential clinical and research relevance. Skeletal Radiol 2023;52(11):2021−30.ArticlePubMedPMCPDF
- [23] Kidd BL, Photiou A, Inglis JJ. The role of inflammatory mediators on nociception and pain in arthritis. Novartis Found Symp 2004;260:122−33. discussion 133-8, 277-9.ArticlePubMedPDF
- [24] Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet 2005;365(9463):965−73.ArticlePubMed
- [25] Miller RE, Kim YS, Tran PB, Ishihara S, Dong X, Miller RJ, et al. Visualization of peripheral neuron sensitization in a surgical mouse model of osteoarthritis by in vivo calcium imaging. Arthritis Rheumatol 2018;70(1):88−97.ArticlePubMedPMCPDF
- [26] Zhu S, Zhu J, Zhen G, Hu Y, An S, Li Y, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest 2019;129(3):1076−93.PubMedPMC
- [27] Maggio N, Shavit-Stein E, Dori A, Blatt I, Chapman J. Prolonged systemic inflammation persistently modifies synaptic plasticity in the hippocampus: modulation by the stress hormones. Front Mol Neurosci 2013;6:46. ArticlePubMedPMC
- [28] Lenz M, Eichler A, Vlachos A. Monitoring and modulating inflammation-associated alterations in synaptic plasticity: role of brain stimulation and the blood-brain interface. Biomolecules 2021;11(3):359. ArticlePubMedPMC
- [29] Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol 2012;4(3):a006049. ArticlePubMedPMC
- [30] Miller RE, Ishihara S, Tran PB, Golub SB, Last K, Miller RJ, et al. An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight 2018;3(6):e95704. ArticlePubMedPMC
- [31] Malfait AM, Miller RE, Miller RJ. Basic mechanisms of pain in osteoarthritis: experimental observations and new perspectives. Rheum Dis Clin North Am 2021;47(2):165−80.PubMedPMC
- [32] Qi L, Tang Y, You Y, Qin F, Zhai L, Peng H, et al. Comparing the effectiveness of electroacupuncture with different grades of knee osteoarthritis: a prospective study. Cell Physiol Biochem 2016;39(6):2331−40.ArticlePubMedPDF
- [33] Shim JW, Jung JY, Kim SS. Effects of electroacupuncture for knee osteoarthritis: a systematic review and meta-analysis. Evid Based Complement Alternat Med 2016;2016:3485875. ArticlePubMedPMCPDF
- [34] Chen N, Wang J, Mucelli A, Zhang X, Wang C. Electro-acupuncture is beneficial for knee osteoarthritis: the evidence from meta-analysis of randomized controlled trials. Am J Chin Med 2017;45(5):965−85.ArticlePubMed
- [35] Liu S, Wang Z, Su Y, Qi L, Yang W, Fu M, et al. A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature 2021;598(7882):641−5.ArticlePubMedPMCPDF
- [36] Wei J, Liu L, Li Z, Lyu T, Zhao L, Xu X, et al. Fire needling acupuncture suppresses cartilage damage by mediating macrophage polarization in mice with knee osteoarthritis. J Pain Res 2022;15:1071−82.ArticlePubMedPMCPDF
- [37] Zhang W, Zhang L, Yang S, Wen B, Chen J, Chang J. Electroacupuncture ameliorates knee osteoarthritis in rats via inhibiting NLRP3 inflammasome and reducing pyroptosis. Mol Pain 2023;19:17448069221147792. ArticlePubMedPMCPDF
- [38] Chen H, Shao X, Li L, Zheng C, Xu X, Hong X, et al. Electroacupuncture serum inhibits TNF-alpha-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway. Mol Med Rep 2017;16(5):5807−14.PubMedPMC
- [39] Ma Y, Guo H, Bai F, Zhang M, Yang L, Deng J, et al. A rat model of knee osteoarthritis suitable for electroacupuncture study. Exp Anim 2018;67(2):271−80.ArticlePubMedPMC
- [40] Luobin D, Huajun W, Yao LI, Jia LI, Ling LI, Yangping G, et al. Electroacupuncture stimulating Neixiyan (EX-LE5) and Dubi (ST35) alleviates osteoarthritis in rats induced by anterior cruciate ligament transaction affecting DNA methylation regulated transcription of miR-146a and miR-140-5p. J Tradit Chin Med 2023;43(5):983−90.PubMedPMC
- [41] Lin J, Wu G, Chen J, Fu C, Hong X, Li L, et al. Electroacupuncture inhibits sodium nitroprusside-mediated chondrocyte apoptosis through the mitochondrial pathway. Mol Med Rep 2018;18(6):4922−30.ArticlePubMedPMC
- [42] Chen W, Zhang XN, Su YS, Wang XY, Li HC, Liu YH, et al. Electroacupuncture activated local sympathetic noradrenergic signaling to relieve synovitis and referred pain behaviors in knee osteoarthritis rats. Front Mol Neurosci 2023;16:1069965. ArticlePubMedPMC
- [43] Barter MJ, Bui C, Young DA. Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs. Osteoarthritis Cartilage 2012;20(5):339−49.ArticlePubMed
- [44] Jang JH, Song EM, Do YH, Ahn S, Oh JY, Hwang TY, et al. Acupuncture alleviates chronic pain and comorbid conditions in a mouse model of neuropathic pain: the involvement of DNA methylation in the prefrontal cortex. Pain 2021;162(2):514−30.ArticlePubMedPMC
- [45] Jiang H, Zhang X, Lu J, Meng H, Sun Y, Yang X, et al. Antidepressant-like effects of acupuncture-insights from DNA methylation and histone modifications of brain-derived neurotrophic factor. Front Psychiatry 2018;9:102. ArticlePubMedPMC
- [46] Zhang L, Lu Q, Chang C. Epigenetics in health and disease. Adv Exp Med Biol 2020;1253:3−55.ArticlePubMed
- [47] Roach HI, Yamada N, Cheung KS, Tilley S, Clarke NM, Oreffo RO, et al. Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum 2005;52(10):3110−24.ArticlePubMed
- [48] Zhu X, Lee CW, Xu H, Wang YF, Yung PSH, Jiang Y, et al. Phenotypic alteration of macrophages during osteoarthritis: a systematic review. Arthritis Res Ther 2021;23(1):110. ArticlePubMedPMCPDF
- [49] Murray PJ. Macrophage polarization. Annu Rev Physiol 2017;79:541−66.ArticlePubMed
- [50] Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018;233(9):6425−40.ArticlePubMedPDF
- [51] Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012;122(3):787−95.ArticlePubMedPMC
- [52] Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 2015;33:257−90.ArticlePubMedPMC
- [53] Wang L, Hauenstein AV. The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med 2020;76:100889. ArticlePubMed
- [54] Van Opdenbosch N, Lamkanfi M. Caspases in cell death, inflammation, and disease. Immunity 2019;50(6):1352−64.ArticlePubMedPMC
- [55] Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol 2020;38:567−95.ArticlePubMedPMC
- [56] Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai) 2005;37(11):719−27.ArticlePubMedPDF
- [57] Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9(1):47−59.ArticlePubMedPDF
- [58] Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol 2013;5(2):a008722. ArticlePubMedPMC
- [59] Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001;107(2):137−48.ArticlePubMed
- [60] Maletic V, Eramo A, Gwin K, Offord SJ, Duffy RA. The role of norepinephrine and its alpha-adrenergic receptors in the pathophysiology and treatment of major depressive disorder and schizophrenia: a systematic review. Front Psychiatry 2017;8:42. PubMedPMC
- [61] Hussain LS, Reddy V, Maani CV. Physiology, Noradrenergic Synapse. Disclosure: Vamsi Reddy declares no relevant financial relationships with ineligible companies. Disclosure: Christopher Maani declares no relevant financial relationships with ineligible companies. Treasure Island (FL), StatPearls, 2024.
- [62] Sharma D, Farrar JD. Adrenergic regulation of immune cell function and inflammation. Semin Immunopathol 2020;42(6):709−17.ArticlePubMedPMCPDF
- [63] Wu H, Chen J, Wang C, Liu L, Wu Y, Zhang Y, et al. beta(2)-adrenoceptor signaling reduction is involved in the inflammatory response of fibroblast-like synoviocytes from adjuvant-induced arthritic rats. Inflammopharmacology 2019;27(2):271−9.PubMed
- [64] Jenei-Lanzl Z, Zwingenberg J, Lowin T, Anders S, Straub RH. Proinflammatory receptor switch from Galphas to Galphai signaling by beta-arrestin-mediated PDE4 recruitment in mixed RA synovial cells. Brain Behav Immun 2015;50:266−74.PubMed
- [65] Tu JF, Yang JW, Shi GX, Yu ZS, Li JL, Lin LL, et al. Efficacy of intensive acupuncture versus sham acupuncture in knee osteoarthritis: a randomized controlled trial. Arthritis Rheumatol 2021;73(3):448−58.ArticlePubMedPDF
- [66] Araya-Quintanilla F, Cuyul-Vasquez I, Gutierrez-Espinoza H. Does acupuncture provide pain relief in patients with osteoarthritis knee? An overview of systematic reviews. J Bodyw Mov Ther 2022;29:117−26.ArticlePubMed
- [67] Yuan XC, Zhu B, Jing XH, Xiong LZ, Wu CH, Gao F, et al. Electroacu-puncture potentiates cannabinoid receptor-mediated descending inhibitory control in a mouse model of knee osteoarthritis. Front Mol Neurosci 2018;11:112. ArticlePubMedPMC
- [68] Yuan XC, Wang Q, Su W, Li HP, Wu CH, Gao F, et al. Electroacupuncture potentiates peripheral CB2 receptor-inhibited chronic pain in a mouse model of knee osteoarthritis. J Pain Res 2018;11:2797−808.ArticlePubMedPMCPDF
- [69] Seo BK, Sung WS, Park YC, Baek YH. The electroacupuncture-induced analgesic effect mediated by 5-HT1-5-HT3 receptor and muscarinic cholinergic receptors in rat model of collagenase-induced osteoarthritis. BMC Complement Altern Med 2016;16:212. ArticlePubMedPMC
- [70] Li A, Zhang Y, Lao L, Xin J, Ren K, Berman BM, et al. Serotonin receptor 2A/C is involved in electroacupuncture inhibition of pain in an osteoarthritis rat model. Evid Based Complement Alternat Med 2011;2011:619650. ArticlePubMedPMCPDF
- [71] Chen T, Zhang WW, Chu YX, Wang YQ. Acupuncture for pain management: molecular mechanisms of action. Am J Chin Med 2020;48(4):793−811.ArticlePubMed
- [72] Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 2008;85(4):355−75.ArticlePubMed
- [73] Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Clin Issues 2005;16(3):291−301.ArticlePubMed
- [74] Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. Eur J Rheumatol 2017;4(3):210−8.ArticlePubMedPMC
- [75] Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets 2009;8(6):403−21.ArticlePubMedPMC
- [76] Palazzo E, Luongo L, Novellis V, Rossi F, Maione S. The role of cannabinoid receptors in the descending modulation of pain. Pharmaceuticals (Basel) 2010;3(8):2661−73.ArticlePubMedPMC
- [77] Fede C, Albertin G, Petrelli L, Sfriso MM, Biz C, De Caro R, et al. Expression of the endocannabinoid receptors in human fascial tissue. Eur J Histochem 2016;60(2):2643. ArticlePubMedPMCPDF
- [78] McPartland JM. Expression of the endocannabinoid system in fibroblasts and myofascial tissues. J Bodyw Mov Ther 2008;12(2):169−82.ArticlePubMed
- [79] Lowin T, Pongratz G, Straub RH. The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB2, TRPV1, TRPA1 and yet unidentified receptor targets. J Inflamm (Lond) 2016;13:15. ArticlePubMedPMC
- [80] Okaty BW, Commons KG, Dymecki SM. Embracing diversity in the 5-HT neuronal system. Nat Rev Neurosci 2019;20(7):397−424.ArticlePubMedPDF
- [81] Jann MW, Slade JH. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 2007;27(11):1571−87.ArticlePubMed
- [82] Haleem DJ. Targeting serotonin1a receptors for treating chronic pain and depression. Curr Neuropharmacol 2019;17(12):1098−108.ArticlePubMedPMC
- [83] Liu QQ, Yao XX, Gao SH, Li R, Li BJ, Yang W, et al. Role of 5-HT receptors in neuropathic pain: potential therapeutic implications. Pharmacol Res 2020;159:104949. ArticlePubMed
- [84] Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet 2021;397(10289):2082−97.ArticlePubMed
- [85] Salaga M, Binienda A, Tichkule RB, Thakur GA, Makriyannis A, Storr M, et al. The novel peripherally active cannabinoid type 1 and serotonin type 3 receptor agonist AM9405 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome. Eur J Pharmacol 2018;836:34−43.ArticlePubMed
- [86] Aguiar DD, Petrocchi JA, da Silva GC, Lemos VS, Castor M, Perez AC, et al. Participation of the cannabinoid system and the NO/cGMP/K(ATP) pathway in serotonin-induced peripheral antinociception. Neurosci Lett 2024;818:137536. ArticlePubMed
- [87] Meneses A, Liy-Salmeron G. Serotonin and emotion, learning and memory. Rev Neurosci 2012;23(5–6):543−53.ArticlePubMed
Citations
Citations to this article as recorded by