Both EA and MA have a significant reduction in pro-inflammatory cytokines (TNF-α, IL-1β) and cartilage degradation biomarkers (MMP-3, MMP-13) and a significant increasing in anti-inflammatory cytokine IL-13. Further, the reduction of TNFα were more significant in EA when compared to MA (p = 0.046). While, there was no significant difference between the EA and MA groups at 8 week in blood cytokine concentrations IL-1β, MMP-3, MMP-13or IL-13.
Our research was based on the hypothesis that both EA and MA could act in an anti-inflammatory manner in individuals diagnosed with mild to moderate knee OA. We found that both 8 weeks EA and MA significantly reduced major pro-inflammatory cytokines (TNF-α, IL-1β) and cartilage degradation biomarkers (MMP-3, MMP-13) and significantly increased the anti-inflammatory cytokine IL-13 compared with pre-treatment. Results in the EA group tended to be slightly better than those in the MA group, that the reduction of TNF-α was more significant in EA when compared to MA. While, there was no significant difference between the EA and MA groups in blood cytokine IL-1β, MMP-3, MMP-13 or IL-13.
A consensus report characterized decreases in individuals’ pain intensity of approximately 10 mm was a clinically relevant pain improvement. By week 8, the mean VAS pain score had decreased by 26.8 units in the EA group and 25.4 points in MA group (greater than MCID). Besides, a 6 points or more improvement in WOMAC physical function was considered to be a clinical improvement. Improvement in WOMAC physical function at 8 weeks was of a clinically relevant in both EA(9.5 points > pre-set MCID)and MA༈8.3 points > pre-set MCID༉. Thus, results of this study demonstrated that both EA and MA had a clinically meaningful benefit in decreasing pain intensity and improving function, although there are no significantly differences between groups due to small sample size.
A number of underlying mechanisms have been proposed to mediate the analgesic and anti-inflammatory effects of acupuncture. Several studies show that both manual and electro-acupuncture produce analgesia through actions in the nervous system and the local tissues [7, 15, 16]. These include opioids which reduce pro-inflammatory cytokines and norepinephrine . A study demonstrated a marked rise in plasma cortisol which brought expected anti-inflammatory effect in rats after EA treatment . The analgesic effect of EA and MA observed in the current study was also believed to be attributed to these previously reported mechanisms.
The development and progression of KOA are now believed to involve inflammation even in the early stages of the disease . Among the pro-inflammatory cytokines involved in KOA, TNF-α and IL-1β are considered the major players; In particular, TNF-α with driving the inflammatory cascade, and IL-1β seems to be associated with cartilage destruction. These two cytokines, which are produced by chondrocytes, mononuclear cells, osteoblasts and synovial tissues, induce the production of a number of inflammatory and catabolic factors .In patients with KOA, levels of both TNF-α and IL-1β are elevated in the synovial fluid. TNF-α and IL-1β can act independently or in concert with other cytokines such as IL-6 and chemokines such as IL-8, MCP-1 and CCl5 [19, 20, 21].Besides, TNF-α and IL-1β could downregulate the synthesis of major extracellular matrix components (MMP-1, MMP-3 and MMP-13) by inhibiting anabolic activities of chondrocytes . A number of anti-inflammatory cytokines, such as IL-13, has been shown to be spontaneously elaborated by synovial membrane and cartilage, and are found in increased levels in the synovial fluid of OA patients . These cytokines exert their anti-inflammatory properties through a number of mechanisms, resulting in a decrease in the production of TNF-α and IL-1β and MMPs. MMP3 and MMP 13 is a major enzyme that targets cartilage for degradation. They not only targets type II collagen in cartilage for degradation, but also degrades proteoglycan, types IV and type IX collagen, osteonectin and perlecan in cartilage . This makes them prime targets for therapeutic strategies. Animal studies provide support for this approach, although only a few clinical studies have investigated the efficacy of blocking these inflammatory cytokines in the treatment of OA. Our result showed that 8 weeks of both EA and MA had an effect resulting in less knee pain and is partly mediated by changes in pro-inflammatory cytokines (TNF-α, IL-1β) and anti-inflammatory cytokine IL-13, as well as cartilage degradation biomarkers (MMP-3, MMP-13) but not all inflammatory cytokines.
There could be several explanations for this apparent discrepancy. First, the levels of inflammatory cytokines were measured in serum, as opposed to synovial fluid, which did not allow us to detect local effects. IL-6 in serum and urine was not associated with clinical measures such as soft tissue swelling . Second, we included patients with mild to moderate knee osteoarthritis, some inflammatory markers maybe undetectable in these people. Sakao et al. reported that IL-6 expression was greater in patient with severe cartilage damage than those with mild cartilage damage . Furthermore, we saw no evidence of any statistical changes in COMP over the course of the 8-week intervention. It is possible that a longer intervention, beyond our 8 weeks could demonstrate an attenuation of cartilage degradation or an increase in formation in the knee OA but this would require further research. We measured total MMP-1 rather than active and it is possible that active MMP-1 may have a closer relationship with knee structural measures, which also needs to be investigated in the future . Finally, given that knee structural changes do not explain all knee pain, the associations of inflammatory factors with structural changes may not translate to their associations with knee pain. Indeed, a few cross-sectional studies have reported inconsistent associations between inflammatory markers and knee pain , so this area remains controversial, and more studies are necessary to identify the roles of inflammation in knee pain.
Our result is in line with previous studies showing that transcutaneous electrical acupoint stimulation (TEAS) diminished the upregulation of pro-inflammatory factors in response to lower limb ischemia-reperfusion in patients undergoing limb ischemia-reperfusion . Moreover, in animal experimental studies it has been shown that acupuncture intervention have positive roles in relieving inflammatory reaction in rheumatoid arthritis by suppressing myocardial inflammatory cytokines (suppressing TNF-α, IL-8, etc.), adjusting inflammatory reaction pathway .
It is important to acknowledge the limitations of the present study. Interpretation of the data was limited by the small number of study participants. This may have influenced our ability to detect significant differences on all of the related inflammatory cytokines, and it is possible that with a larger sample size, more significant changes may be detected. Beyond this, while the focus of this study was limited to specific systemic biomarkers of inflammation and cartilage degradation (and each one of these biomarkers could be influenced by a number of systemic factors), it may be more appropriate to evaluate the effect of EA and MA more directly on the knee joint. While joint aspiration may be painful and invasive, the direct evaluation of biomarkers for inflammation and cartilage degradation from knee joint synovial fluid could allow the effects of acupuncture on knee joint health to be more accurately evaluated. The absence of placebo is a serious limitation in this study and we have tried to overcome this limitation by incorporating a sham treatment group in the future.