The number of osteoarthritis (OA) patients is >300 million worldwide. OA can affect any joint of the body, such as the hip, spine, hand, and especially, the knee [1
]. Knee osteoarthritis (KOA) is characterized by the gradual progression of functional disorders, such as restricted range of motion due to degenerative changes in the knee joints, often with pain and swelling, and KOA impairs the daily life activities of patients [2
]. Moreover, the pathophysiology of KOA is characterized not only by abnormal articular cartilage but also by synovitis, osteophyte synthesis, excessive turnover of subchondral bone, and periarticular soft tissue contracture, which all lead to malfunction of the affected joint [4
]. Although the etiology of KOA is not fully understood, obesity, age, metabolic syndrome, and knee injury are considered to be risk factors [5
], and posttraumatic KOA accounts for 12% of all cases. Knee injury is apparently the main factor for development of KOA in younger people [7
Currently, KOA can be treated surgically and non-surgically. In non-surgical treatments, oral or topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) or oral selective cyclooxygenase-2 (COX-2) inhibitors, intra-articular injection of hyaluronic acid, land-based exercise, dietary weight management with physical exercise, and mind–body exercise (such as Tai Chi and Yoga) have been recommended as effective strategies for KOA patients [8
]. Surgical treatments, such as total/uni-compartmental knee arthroplasty (or osteotomy around the knee), are generally considered when non-surgical approaches have failed to control several clinical symptoms of KOA. Since posttraumatic joint instability due to meniscal tear or anterior cruciate ligament (ACL) rupture can cause destruction of the articular cartilage [9
], orthopedic surgery aims to achieve meniscal repair or ACL reconstruction. These operative procedures can delay KOA progression; however, they cannot completely prevent the devastation of articular cartilage, even after ACL reconstruction [10
]. In fact, KOA degenerative changes tend to be worse when they coexist with meniscal tear due to ACL rupture [11
]. Although various kinds of biochemical mediators, such as interleukin-1β (IL-1β), tumor necrotic factor-α (TNF-α), nitric oxide (NO), and proteolytic enzymes, reportedly can have important roles in the progression of posttraumatic KOA [9
], there are no effective preventive treatments for the pathological changes caused by KOA.
Several compelling reports and a review article on pharmaceutical treatment for KOA by using herbs or flavonoids have been published [12
]. Some plant extracts, such as rosehip and curcumin, have shown therapeutic roles for OA by suppressing inflammatory mediators, including IL-1β, TNF-α, and NO; proteolytic enzymes, such as matrix metalloproteases; and/or a disintegrin and metalloproteinase with thrombospondin motifs. Choi et al. [15
] reported the preventive effect of SKI 306X, a mixture of three herbs, against collagenase-induced arthritis in rabbits. Interestingly, SKI 306X potentially can inhibit proteoglycan degradation, unlike dexamethasone or NSAIDs.
Boiogito (BO), a traditional Japanese herbal medicine (Kampo) composed of six medicinal plants, may also be a potent medication for preventing osteoarthritis. BO is effective for the symptoms of chronic fatigue or hyperhidrosis, as well as leg edema or painful arthritis, and its use for these indications has been approved by the Japanese Ministry of Health, Labour, and Welfare. Some clinical studies have suggested that BO potentially can alleviate inflammation and hydrarthrosis in KOA [16
]. Majima et al. [16
] studied the effects of BO on KOA and joint effusion. Oral administration of BO improved functional capacity while stair climbing, and significantly reduced joint effusion without severe adverse effects. Although BO could have some therapeutic effects for KOA, there is no evidence that BO suppresses KOA progression, especially when evaluating locomotive dysfunction and structural destruction, such as articular cartilage devastation. If a preventive effect against KOA can be demonstrated, BO may become a therapeutic option for early stage KOA. The study’s aim was to evaluate the disease modifying effect of BO on osteoarthritis in a rat model of surgically induced KOA.
Although the pathological mechanism of KOA has not been fully elucidated, KOA is a disease involving articular cartilage but also synovium, subchondral bone, and periarticular soft tissue [25
]. Inflammation of synovium is associated with alterations in the adjacent cartilage. Catabolic and pro-inflammatory mediators, such as cytokines, NO, and prostaglandin E2, produced by the inflamed synovial membrane, lead to excessive production of proteolytic enzymes associated with cartilage degradation [26
]. Current strategies for treatment of KOA are aimed at relieving clinical symptoms, such as pain or swelling of the knee joint and disability of walking, and delaying the progression of KOA, such as cartilage degradation, osteophyte synthesis, or subchondral bone destruction [27
Considering the latency to fall off the rotating drum in the rotarod test in this study, administration of BO improved walking ability in the DMM rat model. Although the rotarod test can detect general locomotive function in experimental rodent models [29
], it can also reflect, at least in part, pain-related locomotive dysfunction derived from surgical invasion, especially within a few days after surgery. In the present study, walking time on the rotarod apparatus was improved by administration of BO not only on days 14–28 (chronic phase) but also a few days after the operation (acute phase) (Figure 4
). Among the crude drugs of BO, Astragalus
], Atractylodes lancea
], Jujube [32
], and Ginger [34
] have been reported to have analgesic actions in various kinds of animal models of pain. BO can potentially relieve acute postoperative pain.
Meniscus extrusion is one of the factors for progression for KOA. In humans, medial meniscus posterior root tear reportedly contributes to meniscus extrusion, possibly because of extensive mechanical loading of the articular cartilage and subchondral bone [35
]. The DMM rat was established to develop KOA by transection of the MMTL, which induces medial meniscus extrusion. We confirmed that the anterior part of the medial meniscus was completely dislocated from the femoral condyle in rats with DMM surgery (Figure 3
). In the present study, the patellar tendon and medial joint capsule were split in the sham group, but KOA did not occur as evaluated by OARSI score. Surgical invasion did not evidently induce osteoarthritic change in the knee joint. Therefore, it is considered that the biomechanical disorder caused by meniscus extrusion strongly influences the development of KOA in the DMM group. Surprisingly, BO inhibited progressive destructive damage of the knee joint, although meniscus extrusion was observed as well in the DMM group. To the best of our knowledge, this is the first report in which BO has been shown to have a preventive effect on posttraumatic KOA.
There has been some basic research suggesting that BO could have a therapeutic effect against KOA, especially on joint fluid retention and the inflammatory response in KOA. Fujitsuka et al. [36
] showed that BO inhibited IL-1β secretion due to synovitis in an ACL-transected rat KOA model. Indomethacin, an NSAID, also has been shown to decrease IL-1β in the synovial fluid but failed to inhibit joint fluid retention in the rats’ knee joints. These results are similar to those in the clinical study mentioned above [16
]. Takenaga et al. [37
] reported a suppressive effect of BO extract on MMP-13 production in rats with adjuvant-induced arthritis as well as an inhibitory effect on the secretion of IL-1β and MMP-13 in cultured chondrocytes. These findings suggest that BO could inhibit the secretion of pro-inflammatory cytokines, decrease excessive joint effusion, and stimulate proper irrigation of the knee joint with joint fluid. Further study is needed to elaborate on the morphopathogenetic and therapeutic mechanism of BO in the DMM-induced KOA model to prove the link between tissue and clinical changes in the rats.
As mentioned above, BO is composed of six crude drugs and contains various kinds of chemical components, but it is not clear which components contribute to the preventive effect against KOA progression. Previous studies have investigated some potential components for alleviating the development of KOA. Sinomenium
stem, a principal crude drug of BO, has been shown to have anti-inflammatory activity [38
]. In animal models of adjuvant and collagen-induced arthritis, Sinomenium
stem improved symptoms and decreased the expressions of pro-inflammatory cytokines, such as IL-1β and TNF-α [39
root also has been shown to have anti-inflammatory activity by decreasing the pro-inflammatory cytokine, TNF-α, although in a rat autoimmune myocarditis model and mouse diabetic model [40
]. Given those findings, a synergistic effect by combining the anti-inflammatory activity of Sinomenium
stem and Astragalus
root may provide the characteristic therapeutic effect of BO against early stage KOA. This ideal combination of chemical components in BO can be applied clinically, such as in the perioperative period for meniscal tears and ACL ruptures, to improve excessive joint effusion and prevent the progression of KOA. Further investigation is needed.
Several limitations of our study need to be considered. First, as mentioned above, we have to elucidate the therapeutic mechanism to prove drug efficacy. We are performing subsequent studies such as immunohistochemical staining and the gene expression of proteins related to cartilage metabolism, including collagen type II and matrix metalloproteinase (MMP)-13. However, the results from this study would be a proposal of a new strategy for posttraumatic KOA. Second, in this study, we estimated the effect for 4 weeks after surgery to assess a preventive effect on the early stage of posttraumatic KOA. However, we need to verify the efficacy longitudinally. When the disease state lasts long, the contralateral side must also be influenced [20
]. Therefore, in the future, we will follow the long-term changes of both knees.