Effects of Acupuncture on Cartilage Degradation and Joint Pain in Osteoarthritis

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]).

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.

Table 1

Acupuncture Protocols and Sham Controls in the Treatment of Osteoarthritis: A Focus on Cartilage Degradation

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].

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 2

Acupuncture Protocols and Sham Controls in the Treatment of Osteoarthritis: A Focus on Pain Modulation

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.