
Osteoarthritis is a chronic degenerative articular disorder. Formation of bone spurs, synovial inflammation, loss of cartilage, and underlying bone restructuring have been reported to be the main pathologic characteristics of osteoarthritis symptoms. The onset and progression of osteoarthritis are attributed to various inflammatory cytokines in joint tissues and fluids that are produced by chondrocytes and/or interact with chondrocytes, as well as to low-grade inflammation in intra-articular tissues. Disruption of the equilibrium between the synthesis and degradation of the cartilage of the joint is the major cause of osteoarthritis. Hence, developing a promising pharmacological tool to restore the equilibrium between the synthesis and degradation of osteoarthritic joint cartilage can be a useful strategy for effectively managing osteoarthritis. In this review, we provide an overview of the research results pertaining to the search for a novel candidate agent for osteoarthritis management via restoration of the equilibrium between cartilage synthesis and degradation. We especially focused on investigations of medicinal plants and natural products derived from them to shed light on the potential pharmacotherapy of osteoarthritis.
Osteoarthritis can be defined as a type of articular diseases resulting from the destruction of articular cartilage and subchondral bone. It is the most common degenerative joint disease, especially in elderly people. The joint stiffness and pain have been known to be the most common symptoms of osteoarthritis and inflammation in synovial tissues, the formation of bone spurs, joint cartilage degeneration, and changes in the underlying bone are its pathological characteristics (Mankin, 1982; Aigner and McKenna, 2002). Mechanical stress, injury of the articular structure, inflammation, oxidative stress, and older age were reported to be the etiological factors of osteoarthritis. However, an effective and definitive method for the cure or, at least, management of osteoarthritis has not yet been developed, since the molecular mechanism of the destruction of articular tissues has not been clearly elucidated (Lim
Thus far, NSAIDs, symptomatic slow-acting drugs for osteoarthritis, analgesics, putative disease-modifying agents, bone-acting agents, and agents for intra-articular injection including corticosteroids and hyaluronic acid have been used as pharmacological agents for the management of osteoarthritis. However, it has been reported that these agents are not efficacious against the root-cause of osteoarthritis, cause many severe side effects, and are not adequate for the long-term management of osteoarthritis (Shen and Gatti, 2013; Lee
NSAIDs are the most frequently used agents for the management of osteoarthritis. They showed moderate activity against osteoarthritic pain; however, it is recommended that NSAIDs be used intermittently or for a short period. NSAIDs can be classified as cyclooxygenase-2 (COX-2)-selective agents and non-selective agents. COX-2-selective agents are celecoxib, meloxicam, rofecoxib, valdecoxib, polmacoxib, and etoricoxib. Non-selective COX inhibitors are diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, azapropazone, carprofen, meclofenamate, tenoxicam, etofenamate, nimesulide, and tiaprofenic acid. Among these, diclofenac, naproxen, celecoxib, rofecoxib, and etoricoxib have been frequently used to manage osteoarthritic pain (Gore
Glucosamine hydrochloride, chondroitin sulfate, diacerein, and glucosamine sulfate are classified as symptomatic slow-acting drugs for osteoarthritis. Prescription-grade chondroitin sulfate and glucosamine sulfate are recommended as first-line agents for the pharmacological management of genicular osteoarthritis. These agents have been reported to show an improvement in physical function and pain in osteoarthritis (Bruyere
Acetaminophen, tramadol, and opioids including oxycodone are used to control the pain in osteoarthritis during a short period, although these agents are not associated with an improvement in pain in the long term (Hochberg
Sprifermin, doxycycline, PG-116800 (a matrix metalloproteinase inhibitor), and cindunistat can be classified as putative disease-modifying agents for osteoarthritis. While clinical trials to prove the efficacy of these agents are ongoing, thus far, these agents have not shown significant improvements in structural changes in the joint (Pavelka
Risedronate, zoledronic acid, strontium ranelate, calcitonin, and vitamin D are classified as bone-acting agents for the regulation of osteoarthritis. They are antiresorptive agents or bone-forming agents. Bone-acting agents showed some potential benefit in the turnover of subchondral bone, although these agents did not show a significant improvement in structural changes of the joint (Baker-LePain and Lane, 2012).
Corticosteroids including triamcinolone, betamethasone, and methylprednisolone and hyaluronic acid are classified as agents for intra-articular injection. Generally, to regulate the acute exacerbation of genicular osteoarthritis, intra-articular injection of corticosteroids is recommended. During the initial 2 to 3 weeks of intervention, intra-articular injection of corticosteroids showed a greater beneficial effect. Furthermore, during follow-up periods of 3 and 6 months, intra-articular injection of hyaluronic acid showed a greater beneficial effect. The combinatorial administration of corticosteroids and hyaluronic acid by intra-articular injection showed a moderate beneficial effect on the pathophysiology of osteoarthritis. However, for long-term pain, intra-articular injection of hyaluronic acid did not show a significant improvement (Bannuru
Inflammation has been reported to be involved in the loss of articular cartilage in osteoarthritis and this mild inflammatory reaction leads to the development of the disease (Kullich
Polysaccharides contained in
In a rat model of collagen-induced arthritis (CIA), the total extract of
Astaxanthin, a carotenoid, showed anti-inflammatory and antioxidative effects on cartilage. It suppressed the expression of MMPs including MMP-13, MMP-3, and MMP-1. Astaxanthin also inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK, and the degradation of inhibitory kappa Bα (IκBα) in interleukin-1β (IL-1β)-stimulated chondrocytes (Chen
Apigenin, an anti-inflammatory flavonoid compound, was reported to suppress the gene expression of MMPs including MMP-1, MMP-13, MMP-3, a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5), and ADAMTS-4, in primary cultured rabbit chondrocytes. It also decreased the proteolytic activity and secretion of MMP-3. Furthermore, intra-articular injection of apigenin inhibited the
Venom from the bee species,
The antioxidative and anti-inflammatory flavonoid compound, kaempferol-3-O-glucopyranoside, also known as astragalin, was reported to inhibit the IL-1β-stimulated activation of NF-κB and MAPK in chondrocytes in patients with osteoarthritis. Astragalin also decreased the production of prostaglandin E2 (PGE2) and nitric oxide (NO) and the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) (Ma
Aucubin, a natural anti-inflammatory product derived from diverse medicinal plants including
Baicalein, a natural product derived from
Polysaccharides present in
Bavachin, a phytoestrogen present in a medicinal plant
Berberine, an anti-inflammatory natural product derived from
Betulin, a natural anti-inflammatory compound isolated from Betulae Cortex, inhibited IL-1β-induced gene expression of MMP-13, MMP-1, and MMP-3 although it stimulated type II collagen gene expression in primary cultured chondrocytes. Furthermore, intra-articular injection of betulin blocked
Biochanin A contained in red clover was reported to block IL-1β-induced expression of MMPs and restore the compromised expression of TIMP-1 via affecting the NF-κB signaling pathway in chondrocytes (Wu
A preparation of
Catechins, the main polyphenolic compounds present in tea, showed potential anti-arthritic effects, and epigallocatechin-3-gallate, a representative catechin, has been reported to exert chondroprotective activity by inhibiting IL-1β-stimulated expression of IL-8, PGE2, and COX-2, in human synovial fibroblasts (Huang
In primary human osteoarthritic chondrocytes, celastrol, a natural product inhibiting heat shock protein (HSP) 90β, showed a suppressive effect on IL-1β-stimulated expression of MMP-13, MMP-3, MMP-1, COX-2, and iNOS-2 (Ding
In an animal model of osteoarthritis established by the intra-articular injection of monosodium iodoacetate, a saponin fraction isolated from
Crocin, a natural compound derived from
Curcumin, a natural compound isolated from
In osteoarthritic chondrocytes, delphinidin, an antioxidative anthocyanidin found in various vegetables and fruits, blocked the expression of COX-2 and PGE2. Delphinidin also suppressed IL-1β-induced NF-κB signaling by affecting IRAK-1 phosphorylation (Haseeb
An aqueous extract of
A natural product present in
GCSB-5 is a standardized extract from a mixture of six herbs including
Gentiopicroside derived from
Ginsenosides isolated from
Honokiol, a major natural compound isolated from
Icariin, a compound derived from
Luteolin, a flavonoid compound derived from Lonicerae flos, blocked IL-1β-stimulated gene expression, secretion, and enzyme activity of MMP-3 in cultured articular chondrocytes. It inhibited the gene expression levels of ADAMTS-4, MMP-13, MMP-1, and ADAMTS-5, and affected the
Monotropein, a compound present in
Morin, a flavonoid compound, has been reported to exert anti-inflammatory, antioxidative, and anticancer effects. Morin blocked IL-1β-stimulated expression of MMP-13 and MMP-3 and promoted the expression of TIMP-1 via suppression of the phosphorylation of ERK1/2 and p38 (Chen
Oleanolic acid, a triterpenoid compound present in various fruit and vegetables, promoted type II collagen gene expression and blocked the gene expression of ADAMTS-5, MMP-1, MMP-13, ADAMTS-4, and MMP-3. Furthermore, it decreased
A preparation of
PG201, a multi-component standardized extract of medicinal plants for managing the symptoms of osteoarthritis, showed a protective effect on the cartilage in an animal model of collagenase-induced arthritis (Shin
Pinocembrin contained in propolis showed a suppressive effect on MMP-13 and MMP-3 expression through affecting the NF-κB signaling pathway in human chondrocytes (Zhang
Piperine, a natural compound present in black pepper (
Prunetin, a natural product found in
Resveratrol, a well-known natural product derived from diverse plants including grapes, has been reported to suppress the expression of iNOS, COX-2, TNF-α, and IL-1β by blocking the NF-κB signaling pathway (Wang
The ethanol extract of Schisandrae Fructus showed chondroprotective activity and inhibited the expression of COX-2, MMPs, and iNOS via suppressing the phosphorylation of JNK, p38, and ERK1/2, and NF-κB signaling, in human chondrocytes (Jeong
Sinomenine, a natural product derived from
Kim
Topical administration of a preparation of
Tetramethylpyrazine present in
Tetrandrine isolated from
A preparation of the total extract of
Willow bark has long been utilized as a folk remedy for managing pain. A preparation of willow bark extract showed an inhibitory effect on the development of oxidative stress and production of proinflammatory cytokines in an animal model of arthritis (Sharma
Wogonin, a flavonoid compound showing anti-inflammatory activity, exerted chondroprotective effects
Ginger,
As mentioned previously, the use of agents for the conventional pharmacological management of osteoarthritis alone cannot address the root-cause of osteoarthritis. Furthermore, these agents show diverse and severe side effects and are not adequate for long-term management of osteoarthritis. On the other hand, a majority of natural products have shown inhibitory effects on proinflammatory cytokine-induced expression and catabolic activity of MMPs in articular cartilage via activation of the NF-κB signaling pathway. They showed suppressive effects on the apoptosis of chondrocytes, induction of extracellular matrix degradation, and decrease in the production of the extracellular matrix, in articular cartilage. However, there is no front-line candidate natural product and/or medicinal plant to reverse or prevent the development of the signs and symptoms of osteoarthritis, despite the many experimental and clinical studies conducted thus far (Fig. 1). Therefore, it is timely to develop an optimal candidate through optimization of the chemical structures of natural products showing the strongest anti-inflammatory, anti-apoptotic, and anti-catabolic activities, to restore the equilibrium between the synthesis and degradation of articular cartilage. Additionally, after joint injury, fibrotic cartilage is generated instead of the normal hyaline cartilage. Thus, it is ideal to develop a novel anti-fibrotic and anti-inflammatory candidate molecule that would facilitate the synthesis of the normal hyaline cartilage in the process of regeneration of articular cartilage.
The authors have declared that there is no conflict of interest.
This research was supported by NRF-2014R1A6A1029617 and NRF-2017R1C1B1005126, Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.
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