CC BY
5
JQY|< ) JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN
Review Article
(E-ISSN 2313-1519)
Osteoarthritis: A contemporary view of the problem, the possibilities of therapy and prospects for further research
Lina Zaripova1, Damira Tazhibayeva2, Natalya Kabdualieva2, Zhaina Aitbayeva2, Gulshakhar Beglarova2, Lazzat Yermentayeva2, Karlygash Niyazbekova2
'Scientific and Innovation Management Department, National Scientific Medical Center, Astana, Kazakhstan 2Department of Pathological Physiology named after V.G.Korpachev, Astana Medical University, Astana, Kazakhstan
Abstract
Osteoarthritis is a chronic degenerative disease characterized by the destructive changes in the articular cartilage, synovitis, subchondral bone sclerosis and osteophyte formation. Today it is the most common joint disease and one of the main causes of disability of elderly people.
This review provides an overview of advances in understanding of osteoarthritis etiology, pathogenesis, histopathology, as well as the results of up-to-date research of the molecular mechanisms underlying this heterogeneous age-related disease at the clinical and fundamental levels.
The article is devoted to a comprehensive review of the osteoarthritis problem, compiled considering the classical understanding of morphological changes, clinical picture, diagnostic methods, and current therapy protocols, supplemented by the modern trends of world research with the prospect of further development and implementation of the latest therapeutic methods, such as nerve growth factor-inhibitors, fibroblast growth factor-18 and stem cells treatments.
Key words: osteoarthritis, pathogenesis, therapy, up-to-date research, biological therapy
Received: 2022-11-04. Accepted: 2022-11-08
This work is licensed under a Creative Commons Attribution 4.0 International License
J Clin Med Kaz 2022; 19(6):6-12
Corresponding author: Lina Zaripova. E-mail: zaripova_lina@list.ru; ORCID: 0000-0001-8728-0225.
Introduction
Osteoarthritis (OA) is the most common chronic disease of the musculoskeletal system, characterized by defective integrity of articular cartilage, subchondral sclerosis, biochemical and biomechanical changes in the extracellular matrix, resulting in the injury of knee, hip, small joints of the hands and spine [1]. According to the generally accepted classification OA may be distinguished between primary (idiopathic) and secondary, which includes post-traumatic OA, metabolic OA (ochronosis, hemochromatosis), endocrine (acromegaly, hyperparathyroidism), neurological and others.
In the global aspect OA represents a significant public health challenge. Being a chronic joint disease OA of the hip and knee is a leading cause of disability in elderly. Moreover, it is the third most rapidly rising disease after diabetes and dementia [2]. With an aging population and an increasing prevalence of obesity worldwide, the burden of OA will continue to rise as the burden on health systems increases [3]. There is evidence
of an increased risk of mortality in connection with OA, which is possibly associated with the development of hypodynamia, metabolic and psycho-emotional disorders, with the background of persistent pain syndrome and low-intensity inflammation, that increases the risk of cardiovascular catastrophes [4].
Etiology and pathogenesis
OA is a clinically heterogeneous disease with the multifactorial etiopathogenesis. The most well-known risk factors for OA include overweight, chronic micro-traumatization of the cartilage due to high physical exertion, trauma, metabolic disorders and hereditary predisposition [5]. Older age (above 65 years), woman gender, occupation with overloading ofjoints, intoxication (smoking, alcohol, uncontrolled medication and heavy metal salts), endocrine and congenital disorders of structure of joints play a role in OA development as the etiological factors.
The pathogenesis of OA is based on degenerative-
dystrophic damage to the articular cartilage, which develops because of imbalance between anabolic and catabolic processes in cartilage and subchondral bone [6]. Articular cartilage consists of a matrix and chondrocytes embedded in it. The extracellular matrix contains proteoglycans and collagen, the content of which decreases in OA, while the structure and biomechanical properties of cartilage are impaired [6]. An impairment of proteoglycans metabolism leads to a violation of the stability of collagen fibers, followed by dehydration and disorganization of the cartilage. The loss of glycosaminoglycans (particularly chondroitin sulphate, as well as hyaluronic acid) leads to a decrease in matrix resistance to the physical stress, and an increase in the sensitivity of the cartilage surface to damage. There is a synthesis and excessive local release of metalloproteinases by chondrocytes, which leads to a progressive slowdown in cartilage repair, an imbalance between the synthesis and degradation of collagen fibers and proteoglycans of cartilage [6]. All together these results in softening, fibrillation, ulceration, and loss of articular cartilage.
The rate of OA cases increases with the metabolic syndrome (MetS) characterised by obesity, elevated level of plasma glucose and triglycerides, reduced the high-density lipoproteins, and hypertension [7]. All these factors have been shown to implicate in the pathogenesis of OA. MetS is a low inflammatory state responsible for glucose and lipid dysregulation leading to increase in the expression of proinflammatory factors and degradative enzymes, lipid deposition in chondrocytes and ectopic inhibition of cartilage matrix synthesis. The increased level of miR-140, miR-27b and hsa-miR-148a caused by proinflammatory environment might affect type II collagen and proteoglycan formation [7]. Hyperglycemia contributes to oxidative stress and increase of glycation end-products leading to cartilage damage. Hypertension with the contraction of small vessels could cause insufficient blood supply compromise nutrient exchange in articular cartilage and potential activation of autophagy that leads to cartilage deterioration [7]. Hypertension probably leads to decrease in synthesis of the synovial fluid, which is necessary for cartilage metabolism. Moreover, ischemia can contribute to microstructural changes of subchondral bone leading to initiation of OA [7].
Currently, the concept of the pathogenesis of OA has undergone some changes: it is no longer considered as only a "degenerative disease", but a disease of active biomechanical and cellular processes with chronic low-intensity inflammation that acts as one of the most important factors in the progression. IL-1 and tumor necrosis factor-a (TNFa) contribute to systemic inflammation, which leads to the activation of NF-kB signaling in both synovial cells and chondrocytes [8]. A wide range of proinflammatory cytokines IL-1, IL-8, IL-17, IL-6, TNFa, the release of free radicals (NO), and transforming growth factor p (TGF-P) contribute to the progression of OA, synovitis and changes in the viability and function of chondrocytes [9]. Up-to-date studies have shown that systemic inflammation can reprogram chondrocytes via inflammatory mediators towards hypertrophic differentiation and catabolic reactions through the activation of NF-kB, oxidative phosphorylation, and autophagy mechanisms [10]. Inflammation usually begins in the synovial membrane of the joint; the biochemical composition of the synovial fluid is disturbed, the loss of hyaluronic acid and degenerative changes in cartilage increase. Thus, the damage of the main structural components of cartilage such as the connective tissue matrix and chondrocytes results in the initial stage to cartilage degeneration, and subsequently changes in the subchondral bone: sclerosis and eburnation of the subchondral bone, formation of osteophytes and subchondral cysts (Figure 1) [6].
Figure 1 - Illustration of osteoarthritis features with respect to healthy joint. Morphological characteristics of OA joint include reduced joint space due to loss of articular cartilage, low-grade synovitis, hypertrophic reaction (sclerosis) in the subchondral bone following by new bone formation (osteophytes), detached fragment of the cartilage displacement to the articular cavity (articular mouse), inflammation of the synovial membrane and weakness of periarticular muscle and ligaments. Created with BioRender.com.
Morphology
Morphological changes in OA include decrease in the joint space due to loss of articular cartilage, hypertrophic reaction in the subchondral bone (sclerosis), new bone formation (osteophytes) at the joint margins, low-grade synovitis with hyperplasia of the synovial membrane, meniscal degeneration, periarticular muscles and ligaments weakness (Figure 1). In the last stage it may be seen an "articular mouse", the detached fragment of the cartilage displaced to the articular cavity. Additionally, the meniscus in OA becomes thinner and damaged.
Diagnosis
Gradual onset of pain, crepitus during movement due to a violation of the congruence of the articular surfaces, limitation of active and passive movements in the joint, atrophy of the surrounding muscles, as well as deformity of the limbs (varus deformity of the knee joints, Heberden's and Bouchard's nodules) with moderate change in laboratory parameters allow to establish the diagnosis of OA.
X-ray is the routinely used examination, golden standard for OA diagnosis that allows to reveal the narrowing of the joint spaces, osteosclerosis and marginal osteophytes (Figure 2) [11].
Figure 2 - Typical X-ray changes associated with osteoarthritis. Osteoarthritis of the left knee with narrowing of intraarticular space, hypertrophic reaction of subchondral bone (sclerosis) and new bone formation (osteophytes at the joint margins; labelled with white arrows), accompanied with severe systemic osteoporosis. Patellofemoral arthritis: degenerative changes underneath the kneecap. Total right knee replacement due to decompensation of osteoarthritis with severe pain syndrome and dysfunction of the joint.
Magnetic resonance imaging (MRI) scan permits visualization of a reactive bone oedema, intra-articular structures and inflammation of soft tissue, degenerated cartilage, or articular mouse in the joint. Computed tomography (CT) can be used for the evaluation of menisci and anterior cruciate ligament if needed for clinical decision [11].
There are no obvious laboratory indicators of OA in casual clinical practice, however, studies demonstrated the new molecules that may be used. Maghbooli et al. (2019) showed significant 23% decrease in serum levels of complement-C1q TNF-related protein 3 (CTRP3) in postmenopausal women in comparison to age-matched controls and suggested that this could be a clinical marker for osteoarthritis [12]. CTRP3 potentially play a role of anti-inflammatory mediator and may works for prevention of OA and reparation of knee cartilage [12].
The main directions of OA therapy
Classical therapy for OA is aimed at reduction of pain, improving the functional state of the joints, and preventing further destruction of cartilage. Treatment recommendations can be conditionally divided into non-pharmacological, pharmacological and surgical [13]. Among the guidelines available for the treatment of OA the most powerful are the global guidelines developed by the Osteoarthritis Research Society International (OARSI) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) updated in 2019.
Both OARSI and ESCEO recommend training, structured exercise, and weight loss as the primary treatment option [13]. The data obtained from the first international survey of OA patients the Global OA Patient Perception Survey revealed that more than 80% of OA patients have comorbidities, especially hypertension, and obesity [14].
The association between metabolic syndrome, type-2 diabetes and OA highlighted the need of low cholesterol dietary with increased consumption of long-chain omega-3 fatty-acids [15]. Benefit of patient's ability to self-manage their condition with diet and exercise was proven and included in OA recommendations. A special role is played by non-drug treatment: patient education aimed at ensuring that patients understand the disease, the need for physical exercises that support the function of the joint, and the use of special devices (kneepads, orthopedic insoles, orthoses and canes) for unloading joint [16]. It is necessary to achieve compliance between a patient and a doctor, the patient understanding that moderate physical exercises (such as swimming, cycling, walking) contribute to reducing of pain and improving the functional activity of the joints [16]. Pharmacological therapy includes the use of paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), the choice of which should be made individually and dictated primarily by a safety assessment. The most serious complications of this therapy are expected from the gastrointestinal tract, and COX-2 inhibitors have the lowest risk; their appointment is justified in a group of patients over 60 years of age, with concomitant diseases and a history of gastrointestinal tract pathology. According to the latest OARSI recommendations, topical NSAIDs are recommended for use in the first line of OA treatment, if ineffective - paracetamol. According to the recommendations of OARSI and ESCEO, paracetamol and NSAIDs should be used only during the period of increased pain syndrome [17]. For persons with concomitant cardiovascular diseases, the use of any oral NSAID is not recommended [13].
The OARSI guidelines for the non-surgical management of knee, hip and polyarticular osteoarthritis emphasize the
appropriate use of intra-articular injections of corticosteroids and hyaluronic acid, as well as the need for aquatic exercise for the treatment of OA [17]. The OARSI and ESCEO guidelines support the use of intra-articular corticosteroid injections in patients with persistent pain unresponsive to topical and oral NSAIDs [13].
Hyaluronic acid drugs for intra-articular administration are indicated in both guidelines [13]. The use of hyaluronic acid is recommended for patients with contraindications to NSAIDs or persisting pain syndrome despite taking NSAIDs. These drugs are well tolerated and have small analgesic effect. Recent studies of the effectiveness of hyaluronic acid injections in patients with osteoarthritis of the knee joint showed a decrease in the severity of pain syndrome according to the visual analogue scale (VAS) and an improvement in joint function according to the Leken index [18].
Symptomatic slow-acting drugs for osteoarthritis (SYSADOA), including chondroitin and glucosamine sulphate, as well as their combination, avocado soybean unsaponifiables and diacerein, are well tolerated by patients and can help improve the effectiveness of treatment and reduce possible functional impairment [19]. Meta-analyses of placebo-controlled trials of SYSADOAs treatment demonstrated evidence of safety and small beneficial effects in patients with OA [19, 20]. OARSI and ESCEO recommendations are divided regarding glucosamine and chondroitin sulphate: they are recommended by ESCEO, while OARSI does not recommend their use, considering them ineffective [13].
Surgical treatment includes arthroplasty, which is prescribed for patients with severe joint dysfunction accompanied by intractable pain syndrome [21]. Lavage of the knee joints with removal of detritus and arthroscopic removal of the "articular mouse" can also reduce pain but does not stop the disease progression [21].
COVID-19 and OA
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became an important issue for healthcare in the worldwide for a few years. It affected different organs and systems and may potentiate development of a range of autoimmune disease, including arthritis, however, there is a lack of data about OA cartilage degeneration due to COVID-19 [22]. Endothelial and adipose tissue dysfunction induced by SARS-CoV-2 through its influence on angiotensin-converting enzyme 2 (ACE2), adiponectin concentration, and apoptosis lead to a meta-inflammation [22]. Acute pain is associated with the production of pro-inflammatory cytokines, including CCL2/3/4, CXCL2, IL-1, IL-6 and TNF [22]. Hypovitaminosis D, hypocalcaemia followed by demineralization and bone fragility in patients with COVID-19 point towards bone aging, while arthralgia and myalgia resemble OA aging characteristics and may be classified as early OA-like phenotype of COVID-19 [22].
COVID-19 negatively influences on patients with chronic diseases including OA. Delay of nonemergency procedures due to COVID restrictions lead to a significant number of postponed joint replacement operations or cancellations of surgical or therapeutical procedures [23]. COVID control have reduced access to healthcare services most of them became through remote working (telemedicine, telehealth, virtual consultations) [24].
OA usually going with comorbidities such as cardiovascular disease, diabetes, and obesity, that increase the risk of COVID-19 infection and its severity. Restrictions of access to exercise facilities may lead to limitations in range of motion,
hypodynamia and subsequent muscle atrophy of individuals with OA. So even in COVID quarantine patients are strongly advised to continue to exercise near or at home (walking, yoga, tai chi) and reduce weight with a healthy diet [23].
The question about routinely prescription of NSAIDs in OA was highly debatable. Research revealed no negative effect of prescribed NSAIDs on COVID-19 related deaths [24].
New therapeutic opportunities and prospects for further research
Throughout the history of OA research several therapeutic approaches have been proposed (pharmacological treatment, physiotherapy, acupuncture), but none of them leads to a complete cure or even to reliable pain relief and improvement joint function. The absence of effective disease-modifying therapy induces a vast of OA research worldwide.
Intra-articular platelet rich plasma
Intra-articular platelet rich plasma (PRP) appears to be a promising therapy in the last few decades. PRP preparations are prepared by separating autologous blood (about 100 ml) by a two-stage centrifugation method, which separates plasma and cellular elements. The concentration of platelets in this preparation is about 1 million/^l, which is about 5 times higher than the content in native blood. Platelets are activated by adding thrombin or fibrin "matrix", and then the resulting clot ("gel") is injected with a syringe into the affected area. Platelets secrete platelet growth factor, TGF-p, fibroblast growth factor, insulinlike growth factor 1 and 2, which act as tissue hormones and factors of migration and differentiation of stem cells [25]. Some authors have noted a significant reduction in pain after PRP compared with baseline in patients with knee OA, regardless of age, sex, severity and body mass index [26]. The combination of platelet-rich plasma with hyaluronic acid administered intra-articularly to patients with OA showed the same efficacy as PRP alone [27]. However, intra-articular PRP did not show a significant advantage over placebo to add this method to the recommendations for the treatment of knee OA [28, 29]. Cellular therapy
Cell therapy methods in the treatment of OA are being widely researched. Mesenchymal stem / stromal cells (MSCs) have gained significant popularity due to the enormous opportunities, lack of ethical limitations and risks usually associated with other stem cells such as embryonic stem cells. MSCs have been identified in the synovial fluid of healthy people; however, with arthritic changes, the number of MSCs increases significantly [30, 31]. Jones et al (2008) found that the level of MSCs obtained from synovial fluid is seven times higher in OA compared with the control group [32]. It was known that MSCs can play a positive role in the restoration of cartilage tissue in the pathogenesis of arthritis. De Sousa et al (2014) emphasize that these cells maintain homeostasis, involved in the restoration of joint tissue and restore the balance between catabolism and anabolism of cartilage tissue [33]. MSC studies have demonstrated cartilage remodeling in a mouse model of OA, as well as a decrease in pain due to damage to the subchondral bone when using the MSC secretome. After preclinical evaluation in experimental animal models, MSCs began to be used in single studies in patients with OA. However, according to the Canadian recommendations for intra-articular injections for osteoarthritis of the knee, there is currently insufficient evidence to recommend MSCs for the treatment of OA [29]. Thorough, well-planned clinical trials are required to establish the safety, efficacy, and cost-effectiveness of MSCs before including in the treatment protocols.
Journal of Clinical Medicine of Kazakhstan: 2022 Volume 19, Issue 6
A promising method for the treatment of OA may be induced pluripotent stem cells (iPSCs). Patient-specific stem cells can be created by reprogramming a somatic cell to a pluripotent state, for example, by transferring its nucleus to an oocyte. SOX2 and OCT4 in combination with KLF4 and cMYC also promote the reprogramming of human fibroblasts into iPSCs. These studies demonstrated that pluripotency can be restored in a terminally differentiated cell, and suggest that these cells will be able to support the infinite production of functional chondrocytes [34].
Autologous chondrocyte transplantation was proposed as a variant of cell therapy for OA in the recent years and shown to be effective in restoring hyaline cartilage [35].
Monoclonal antibodies
One of the main therapeutical directions recently explored is monoclonal antibodies, such as anti-TNFa agents (adalimumab, infliximab and etanercept) and IL-1 inhibitors (anakinra, canakinumab), which are successfully used for rheumatoid arthritis, psoriatic, enthesitis-related and juvenile idiopathic arthritis treatment [36, 37]. However, they did not demonstrate statistically considerable efficacy in OA: adalimumab did not significantly decrease a pain, synovitis or bone marrow lesions in patients with erosive hand OA [38]. IL-1 targeting therapies also failed to bring remission in OA: IL-1a/p immunoglobulin had no effect on pain or imaging outcomes in patients with erosive hand osteoarthritis [39] and minimal decrease in pain score with no improvement in synovitis of knee compared to the placebo group [40]. Data about IL-6 involvement in OA pathogenesis promoted OA research with tocilizumab, an antibody against IL-6 receptor, though no efficacy was found in 83 patients with hand OA [41].
Biological therapy also includes the antibodies against nerve growth factor (NGF) [42-44]. Nerve growth factor (NGF) is the major mediator of pain, binds to tropomyosin receptor kinase A and p75 on nociceptive neurons [45]. Taking into account the key role of pain in OA and the side effects associated with long-term use of NSAIDs and opioid analgesics, anti-NGF antibodies became a promising therapeutical tool for OA treatment. Anti-NGF monoclonal antibodies currently include 3 medications (tanezumab, fasinumab and fulranumab). The drugs are currently under III phase clinical trials, but promising clinical results such as pain relief and physical function improvement have already been obtained [42, 43]. However, despite the high expectation the side effects of these drugs have to be carefully analysed before anti-NGF can enter the therapeutic arsenal for OA.
The search for the disease-modifying drugs for OA continues, and fibroblast growth factor (FGF)-18 may take this position. FGF-18 is known as a molecule that protects articular cartilage due to anti-catabolic effects mediated by tissue inhibitor of metalloproteases (TIMP)-1, stimulation of chondrocytes and maintenance of cartilage homeostasis [46]. Recombinant human FGF-18 (sprifermin) is considered a disease-modifying drug used as an intra-articular injection, and it has been shown to reduce the injury of cartilage [46]. Moreover, it was demonstrated that the intra-articular administration of 100 ^g of sprifermin every 6 or 12 months resulted in significant improvement in total femorotibial joint cartilage thickness after 2 years [47].
Others: metformin
Nowadays there are conducted the range of studies dedicated to the effect of various substances that may affect the processes of destruction and formation of cartilage. For example, Li et al. (2020) conducted an experimental study of the effects of metformin on cartilage in a mouse model of
osteoarthritis. It is known that metformin can induce adenosine monophosphate-activated protein kinase, which is postulated as a potential therapeutic target for the treatment of OA. In vitro experiments have shown that metformin not only lowers the level of matrix metalloproteinase 13, but also increases the production of collagen type II, thereby reducing the severity of structural damage in OA and reducing pain [48].
Further directions
A number of studies have been carried out using large-scale genome-wide screening of miRNAs expressed in osteoarthritic cartilage or subchondral bone, microRNAs (miRNAs) have been identified, which play an important role in cartilage homeostasis and the OA process and can potentially be used to modify the disease [49]. miRNAs are short non-coding RNAs (18-14 nucleotides) that bind to one or more mRNAs to regulate their expression by inhibiting the translation or increasing mRNA degradation. Most of the published studies focused on one or two miRNAs and are based on the hypothesis that they target the gene that plays an important role in the pathogenesis of OA. For example, miR33a regulates cholesterol metabolism in chondrocytes via the TGF-pi/Akt/SREBP-2 pathway, while ABCA1 and ApoAl genes associated with cholesterol efflux [50]. It was found that MiR-370 and miRNA-373 regulate the expression of SHMT-2 and MECP-2 in chondrocytes [51]. MiR-16-5p has been shown to regulate the expression SMAD5 in cartilage [52], while miRNA-26a-5p regulates the expression
of inducible nitric oxide synthase (iNOS) by activating the NF-kB pathway in chondrocytes in OA [53]. The expression of osteopontin in cartilage is regulated by miR-127-5p [54], while miR-139 inhibits the proliferation and migration of chondrocytes [55]. The results of these studies may contribute to the development of radically new methods of therapy for OA in the nearest future.
Conclusion
Despite the huge amount of data of the OA the current treatment options are very limited with no effective cure that might stop or slow down the progression of this disease. The therapeutical options include NSAIDs, paracetamol, non-opioid analgesics, steroids, SYSADOAs, non-pharmacological and surgical methods. In recent years, significant progress has been achieved in understanding of the pathogenetic mechanisms of OA and promising options for biological and cell therapy have been proposed. However, further clinical studies are needed to examine their safety and efficacy.
Disclosures: There is no conflict of interest for all authors.
Acknowledgements: None.
Funding: None.
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