Disclaimer: The following text was written by our own team of pharmacists and medical experts – Dr. Disha Trivedi; Dr. Eva Künnemann and Senior Pharmacist Riya Jayapal Roja. It has been published in www.academia.edu
Abstract
The use of natural compounds has been significant for human health since centuries. However, only with molecular techniques and cell biology experiments, the function of these interactions can be shown and their therapeutic use in medicine be proven. In this review, we show the pathology of osteoarthritis and rheumatoid arthritis, a disease condition affecting millions of people worldwide and we describe herbal materials that are used for arthritis treatment. In detail, we describe how different plant substances, that is, curcumin and several ingredients of rosehip, can interact with cartilage compounds and reduce the inflammatory reaction by specifically interacting with cellular pathways. Arthritis forms a vicious cycle, where upon overuse of a joint or an autoimmune reaction inflammation and pain occur. These are marked by specific molecular patterns and immunological pathways that lead to chondrolysis and destruction of cartilage. Natural plant substances can influence these pathways and help to break out of the vicious cycle and to find a way for stopping the disease or even to regenerate and heal injured cartilage. In conclusion, rosehip, curcumin and other natural remedies are effective treatments and combinations are possible. Bioavailability of the substances is important and can be increased with specific enhancers. We also discuss that targeting pain only without treating cartilage degeneration can lead to unnoticed further irreparable decay and advice to treat pain and joint health at once. Additionally, regular movement of the joints is necessary for natural compounds to act in the human body and provide wellness.
1. Introduction
Don’t complain—ask grandmother. This wisdom used to apply in former times in many families because grandma knew what to do when it came to the ailments of her loved ones. She knew recipes for fast-acting home remedies in abundance. She had a lot of practical knowledge in the field of health. This enabled her, as if by magic, to produce a cough tea or a remedy against an infection.
The Middle Ages were the heyday of medicinal plants. They were obtained from nature and specially created gardens. After herbs had only been collected for a long time, in Europe Charlemagne (768–814) ordered their systematic cultivation [1]. Herb gardens were subsequently laid out primarily by the monasteries, but also emerged at the courts. The profession of the wise herbalist, who collected the plants in the vicinity of the settlement and who knew how to use them against various diseases, developed among the people. Among many natural healers, Hildegard von Bingen is very famous. She was an abbess and naturopath who gave recommendations to help with all kinds of complaints concerning the human body [1]. We still can draw on this knowledge today. The herbal healers and the wise women were sometimes called hedge witches, as they had special knowledge so it seemed magical what they did. Therefore, people are not always trusted and a lot of what they did was secret.
Meanwhile, this was changed. Now everyone can access lots of information, and researchers must explain their findings to the public. In fact, with science making progress, we can more and more see in detail the effects of plant remedies on humans and their health, for example, the molecular binding patterns and the pathways in a cell that are influenced by a compound. In that way, the positive actions of plant ingredients and the advantageous interaction of plant substances with the human body can be proved now. As traditional healers throughout the world have relied for the treatment of arthritis on herbal medicines in their practices for millennia [2], long-term use of natural substances is known. In medicine, many unique plant effects of special substances on human tissues have only been understood within the last few years.
At MVS Pharma, natural products and interactions are researched to understand and develop new functional products. In this review, we give an overview of arthritis, its different forms, and the pathway of inflammation that forms a vicious cycle. There is a vast number of studies showing that many herbal products have pertinent medicinal effects for the management of osteoarthritis (OA) as well as rheumatoid arthritis (RA). Many patients continue to seek care from complementary and alternative providers to obtain more effective and less toxic treatments. We enumerate the known therapies and what are the drawbacks there as well as the advantages of natural compounds. Finally, we focus on two plants and extracted substances. First is rosehip, which contains several useful ingredients. Second, we show in detail the various interactions of curcumin in the prevention and therapy of arthritis. A broad overview of the research in the field comprising the interaction of herbal substances from rosehip and curcuma within the joints affected in arthritis is summarized in this review.
Download the full research document here.
2. Description of arthritis
Arthritis is an acute or chronic joint inflammation that often co-exists with pain and structural damage [3]. There are many types of arthritis, whereby the most common forms are OA and RA [4]. Arthritis leads to a vicious cycle where inflammation continues during the course of the disease, see Figure 1. Our goal at MVS Pharma is to find a way to escape from this circularity.
RA, on the other hand, is an autoimmune systemic inflammatory disorder. An interplay between several genetic factors (HLADRB1 and others) and environmental factors, like smoking, leads to activation and dysfunction of the immune system and subsequently to inflammation in RA [5]. RA is an autoimmune syndrome that often affects the hands and feet [4]. The etiology of arthritis varies with the type of arthritis. Figure 2 shows the most frequent forms of arthritis, OA, and RA with their general features. It is important to differentiate between OA and RA to use the appropriate therapy.
Figure 1
The vicious cycle of arthritis.
Figure 2
Representation of the features of osteoarthritis and rheumatoid arthritis.
2.1. Osteoarthritis
OA is currently the fourth leading cause of disability worldwide as it leads to chronic incapacitating disease of joints. More than 30% of women have OA by age 65. It is a joint failure that occurs due to pathological alteration in all structures like bone, cartilage, and synovium [6]. It usually affects the hip, knee, cervical, and lumbosacral spine, first metatarsal phalangeal joint, and the base of the thumb. The wrist, elbow, and ankle are frequently spared. The etiology of OA includes age, sex, heredity, obesity, previous knee injury, etc. [7–9]. Other risk factors for OA comprise prior joint trauma and a sedentary lifestyle [9]. Some genetic factors have additionally been described such as mutations in genes encoding types II, IV, V, and VI collagens [10, 11]. The probability of OA is increased by age due to the decreasing ability of chondrocytes, the cells forming cartilage, to sustain the structural integrity of this formation [12].
OA occurs in phases, where first within the healthy joint cartilage decreases (compare Figure 2). In a later stage, the cartilage degeneration continues, and the bone is also affected. Stiffness starts to occur until in the final stage the joint ossifies totally. During early stages, healing is possible while later it gets more and more difficult to regenerate the cartilage. Therefore, although prevention and healing are the aim, already a stop of the aggravation can be a success.
In former times, OA has usually been observed as a non-inflammatory condition [13], but improved detection approaches show that inflammatory pathways are upregulated in OA [14] with, for example, a low-level increase in C-reactive protein [15]. Still the pathophysiology of OA is not fully understood and involves numerous inflammatory and oxidative events.
Kraus et al. [16] proposed that the altered inflammatory state is the underlying cause of OA, and mechanical stress is the inducer. Patients with the arthroscopic manifestation of early OA and knee pain but normal radiographs (n = 10, mean age: 63.4 years) exhibited significantly higher immune histological measures of inflammation, such as tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB), and cyclooxygenase-2 (COX-2) in synovial tissue compared to late OA patients who required arthroplasty (n = 15, mean age: 74.4 years) [17].
The NFκB signaling pathway is linked with the proinflammatory environment since it releases numerous cytokines. The stimulation by TNF-α and IL-1β signals the activation of I Kappa Beta Kinase (IKK), which results in the phosphorylation of IKB-α. The resulting degradation products act in the nucleus, which leads to the activation of several genes responsible for the production of several inflammatory and pro-apoptotic factors [18, 19].
In the healthy body, homeostasis is found, where equilibrium of components of extracellular matrix (ECM) and cartilage-degrading enzymes occurs. However, during OA, accelerated cartilage degradation is imposed by an increase of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase thrombospondin motifs (ADAMTS) [20].
The inflammatory stimulus is in fact associated with the release of ADAMTS4 and ADAMTS5, which are aggrecanase and slip aggrecan, the main glycosaminoglycan of the cartilage. The MMP-3 plays a role in the synergism of proteoglycans degradation after aggrecans degradation. MMPs are correlated mainly with the degradation of type II collagen and play a crucial role in cartilage destruction. MMP-1, MMP-3, MMP-9, and MMP-13 are closely related to this process. MMP-13 is not found in healthy cartilage. The inflammatory state and the occurrence of IL-1β and TNF-α also stimulate the release of MMPs.
Alarmins, damage-associated molecular patterns (DAMPs), produced as standard cellular components from degraded ECM are also increased in OA. These molecules bind to other cells’ membranes or intracellular receptors, which trigger the inflammatory responses. DAMPs can attach to the toll-like receptor family, supplementing the inflammatory activation and contributing to OA pathogenesis. This process in the joint results in an imbalanced release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which have an important role in the development of OA [21].
The release of cytokines is detected in synovial fibroblasts, macrophages, and chondrocytes. Chondrocytes can experience apoptosis due to extrinsic factors or mitochondria-associated signaling pathways connected to oxidative stress and lysosomal dysfunction. Additional inflammatory markers like COX-2, released by synovial monocytes, and prostaglandins-2 are also involved in the inflammation in OA [21–24].
The synoviocytes, the cells that line the inner surface of joints and tendon sheaths, can also produce inflammatory cytokines, biomarkers that raise inflammation and cartilaginous destruction [25–28]. Additionally, mechanical load is a serious risk factor for the development of OA. This arises from an excessive mechanical stress over a normal joint due to obesity or occupational risk. It originates from a joint that has waisted its mechanoprotective mechanisms [20].
Normally, mechanoprotection is built on a stable joint, healthy dense cartilage, and sturdy muscle, which support the joint. Imbalance in these variables is related to a pro-inflammatory environment named mechanoflammation. It includes the stimulation of the TGF-β-activated kinase 1 (TAK1), which is closely linked with the upregulation of mitogen-activated protein kinases like p38 and c-Jun N-terminal kinase, and NFκB signaling. TNF-α and IL-1β similarly stimulate TAK1 and toll-like receptor (TLR) ligation. TAK1 stimulation leads to related pathways linked with the control of aggrecan degradation. In addition, it also stimulates nerve growth factor, which is a key mediator of pain in OA [29, 30].
Similar to the destruction of cartilage for the reasons stated above, a disrupted bone resorption procedure is observed and osteoclastogenesis occurs. The receptor activator of NFκB ligand (RANKL) is released by osteoblasts and displays an affinity for RANK, which leads to phosphorylation pathways resulting in the activation of NFκB. The osteoprotegerin also can bind to RANK, which leads to apoptosis of mature osteoclasts [31, 32].
2.2. Rheumatoid arthritis
RA is characterized by persistent joint synovial tissue inflammation. Over the period, bone erosion, destruction of cartilage, and complete loss of joint integrity can also occur. Finally, multiple organ systems may be affected. RA is the most common inflammatory arthritis, affecting 0.8% of the adult population worldwide. Onset generally occurs between 30 and 50 years of age. Female sex, a positive family history, older age, silicate exposure, and smoking are associated with an increased risk for developing RA [33–35]. Consumption of more than three cups of coffee daily—particularly decaffeinated coffee—also may contribute [36]. High vitamin D intake, tea consumption, and oral contraceptive use are associated with decreased risk [35, 37]. Humidity and weather also play important roles in developing RA [38, 39].
Joint damage in RA begins with the proliferation of synovial macrophages and fibroblasts after a triggering incident, possibly autoimmune or infectious. Lymphocytes infiltrate perivascular regions, and endothelial cells proliferate. Neovascularization occurs then. Blood vessels in the affected joint become occluded with small clots or inflammatory cells. Over time, inflamed synovial tissue begins to grow irregularly, forming invasive pannus tissue. Pannus invades and destroys cartilage and bone. Multiple cytokines, interleukins, proteinases, and growth factors are released, causing further joint destruction and the development of systemic complications [33].
3. Available therapies for arthritis and drawbacks
Pharmacological management of OA typically involves analgesics such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids. It is mainly used for the treatment of symptoms but does not affect the underlying pathogenesis of articular diseases, thus they have a minimal role in modifying the disease course. Paracetamol, which for a decade was regarded as a safe drug, has now been reported to enhance the risk of upper gastrointestinal problems [40]. There has been an increase in the use of disease-modifying osteoarthritic drugs (DMOADs) whose actions are basically aimed at preventing the breakdown of articular cartilage [41]. Drugs belonging to this group are glucosamine, chondroitin sulfate, and diacerin but there are conflicting reports regarding their efficacy. In this context, there has been a search for new alternative compounds that could minimize pain and stiffness without serious side effects. It is therefore important that alternative OA treatments are evaluated, which could be both effective and well tolerated. Medicinal plants have a long tradition in the treatment of OA.
The exact etiology of RA remains unclear, whereas current medications for RA include NSAIDs, corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), and biological response modifiers [42]. However, these drugs have a variety of side effects. NSAIDs may endanger the lives of patients due to the adverse effects of upper gastrointestinal bleeding, as well as adverse reactions in the liver and kidneys [43]. In addition, headaches, cognitive disorders, and allergic reactions often make patients stop treatment, thus greatly limiting the use of NSAIDs. The long-term application of corticosteroids can induce infection, hypersplenism, hypertension, osteoporosis, and fractures [44]. DMARDs cause vomiting, diarrhea, rashes, decreased white blood cell levels, and impaired liver and kidney functions [45]. Biological agents with high pharmacological selectivity and fewer side effects are new choices for the treatment of RA [46]. However, these biological agents are expensive and many patients cannot receive biological therapy [47]. Therefore, it is necessary to search for some medicines with good therapeutic effects, fewer side effects, and low cost.
In recent years, anti-TNF-α therapy has been introduced as a new therapeutic approach for intervention in arthritis. Although anti-TNF drugs such as etanercept and infliximab show encouraging results in arthritis patients, some individuals fail to respond to treatment. Moreover, adverse side effects of these drugs have recently come to light, the most important being impairment of the patient’s immune and surveillance systems, which will increase susceptibility to opportunistic bacterial and viral infections and to the spontaneous development of tumors. Therefore, it is of considerable clinical interest to identify novel naturally occurring pharmacotherapies for OA and RA [48].
Nanoparticle-based therapy offers some advantages over conventional therapies. These particles can stabilize encapsulated drugs and make controllable drug release, which lead to prolonged drug retention time [49]. Rationally designed nanoparticles can diffuse and penetrate the joint tissue to facilitate cartilage repair. Nanoparticle-based delivery systems can target specific sites actively or passively, which enhances therapeutic effects and lowers the side effects of the loaded drugs [50, 51].
Despite the development of various nanoparticles for the treatment of OA and RA, none have been approved for clinical use yet. Several barriers still exist in the clinical translation of injectable nanoparticles for OA and RA treatment. One important consideration for the clinical translation of nanoparticles is their toxicity, distribution, and final fate in the body, especially for newly developed nanoparticles. Biodegradable synthetic polymers have been widely utilized for drug delivery in nanotechnology. A potential disadvantage of acidic degradation products is that they may worsen cartilage inflammation and matrix degradation [52, 53].
