The Diversity of Arthritis 101: Osteoarthritis
Foreword
Arthritis is a debilitating, chronic condition that mainly targets the joints. Arthritis is mistakenly simplified to a single condition known as osteoarthritis. For this reason, arthritis is often viewed as a degenerative disease that solely appears in older people. Hence, this 101 series will give insights into the heterogeneity of arthritis, educating individuals about the array of pathophysiological mechanisms and symptoms that can manifest in affected individuals. This series of articles aims to dispel the stigma attached to arthritis which labels it as a disease of the elderly by evaluating novel research which portrays the complexity of the pathophysiology of multiple forms of arthritis. Although it is not possible to illustrate the full diversity of conditions affecting the joints, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gout and infectious arthritis will be discussed in the following 101 series.
This 101 series is divided into six articles, including:
The Diversity of Arthritis 101: Osteoarthritis
The Diversity of Arthritis 101: Rheumatoid Arthritis
The Diversity of Arthritis 101: Psoriatic Arthritis
The Diversity of Arthritis 101: Ankylosing Spondylitis
The Diversity of Arthritis 101: Infectious Arthritis
The Diversity of Arthritis 101: Gout
The Diversity of Arthritis 101: Osteoarthritis
Arthritis encompasses a range of unique diseases which predominantly target joints (Versus Arthritis, 2018). Anatomically, there are two classifications of joints: synovial and solid joints. Although cartilaginous joints (a form of solid joint) can be impacted by arthritis, it is most often seen that synovial joints are under them most stress from the condition. Synovial joints are found where two bones articulate with each other. A synovial joint contains a membranous capsule, known as the synovium, filled with lubricating fluid in the joint space (synovial fluid). The ends of the bones are protected by articular cartilage, which is composed of specific cells, known as chondrocytes, embedded in extracellular matrix (ECM) components, like Type II collagen and proteoglycans. Chondrocytes are responsible for synthesising the ECM that makes up cartilage (Ralston & Al, 2018). With different types of arthritis, the number of joints impacted can vary. Monoarticular arthritis refers to the affliction of a single joint, oligoarticular arthritis can affect two to four joints while polyarticular arthritis is used to describe cases where more than four joints are implicated in the disease. Synovial joints that are habitually affected include small joints of the phalanges, knee joints, hip joints and shoulder joints. Intervertebral discs of the spine are examples of cartilaginous joints that can be vulnerable to arthritic degradation (Shayan Senthelal & Thomas, 2018).
Osteoarthritis (OA) is the most prevalent form of arthritis, with approximately 240 million people being affected worldwide (Allen et al., 2021). OA can be primary or secondary. Primary arthritis has no definitive cause and is generalised to be a product of "wear and tear". Secondary OA attributes the development of arthritis to an existing injury or a congenital bone defect (Sen & Hurley, 2023). As primary OA has a higher incidence rate than secondary OA, the main population affected are individuals older than 45 who have had progressive joint degradation (Centers for Disease Control and Prevention, 2019). Yet, this does not exempt younger individuals from being diagnosed with OA, especially those who put a lot of strain on their joints by working as professional athletes (Amoako & Pujalte, 2014). The incidence of OA can be exacerbated in certain subpopulations. Women, people of colour, individuals with obesity, and even people of lower socioeconomic status are at an increased risk of experiencing OA, depicting how individual differences and social determinants can create health inequality in arthritic patients (Luong et al., 2012). OA has cardinal symptoms which can be burdening both physically and mentally. These include joint pain after activity, stiffness, loss of joint function and buckling of joints (Hunter et al., 2008).
The aim of this article is to give an insight into the pathophysiology of OA, describing the possible mechanisms that cause OA symptomatology. The current treatments of OA will be addressed, along with recent research findings that explore the complexity of arthritis and future therapeutic options. A case study of a patient with OA will also be described to portray OA in a real-life setting.
Pathophysiology of Osteoarthritis
Degradation of Articular Cartilage
The initial stage of OA involves a disturbance in chondrocyte function, leading to the progressive degradation of articular cartilage found in synovial joints. It is suspected that the disturbance is brought about by an imbalance in the rate at which new cartilage is synthesised (anabolic pathway) and existing cartilage is removed (catabolic pathway), the latter becoming the dominant pathway (Grässel et al., 2021). An injury, such as in the case of post-traumatic OA (Kramer et al., 2011), or an alteration in a gene caused by an interaction with environmental factors (epigenetic change) can disrupt the structure of the synovial joint (Núñez-Carro et al., 2023). The shift from anabolism to catabolism in chondrocytes can be mediated by DNA methylation and histone modification; these are examples of epigenetic changes that involve molecular changes which can regulate gene expression. Epigenetic regulation of genes that encode for ECM degradation enzymes, inflammatory mediators and reactive oxygen species (reactive, oxygen-containing molecules that can be toxic for cells) have been found. These modifications have been found to promote chondrocyte death and senescence (loss of the ability to divide) while also inhibiting the synthesis of new cartilage (Tong et al., 2022). The aberrant function of mitochondria, an intracellular structure that synthesises energy for cells, has also been implicated in OA pathophysiology. Dysfunction of mitochondria has been studied as a significant sign of ageing (Zhang et al., 2023). It is thought that multiple factors, both genetic and environmental, can decrease a mitochondria’s ability to produce cellular energy and instead, cause it to produce abnormal amounts of reactive oxygen species. The reactive chemicals can, in turn, up-regulate matrix metalloproteinases (enzymes that degrade components of the ECM). They can also switch the production of type II collagen to type I collagen, which weakens and reduces the elasticity of the joint matrix, and increase cell death (He et al., 2022; Salman et al., 2023). The complex set of molecular events that cause the degradation of articular cartilage can be set into motion by joint instability, which can be a consequence of joint malformations present at birth (such as congenital dysplasia), or caused by injuries (Poulet, 2017). Obesity can also be a risk factor for OA. Although it is usually associated with increased mechanical stress on the joints, the risk can arise because it is an example of a metabolic syndrome; metabolic disruptions may cause aberrant molecular events which induce OA (Courties et al., 2017).
Inflammatory Pathways
Even though the order of events is unclear, researchers now agree that inflammation of the joint is a principal disease mechanism in OA. OA is mistakenly presented as a disease caused by ‘wear and tear’, an unavoidable consequence of mechanical stress on the joint. This often limits the advice given to a patient on how to deal with their condition. Inflammation is the body’s natural response to infection and damage (van den Bosch, 2018). The process involves increasing vascular permeability in the target area, promoting migration of immune cells—such as macrophages and neutrophils, which are adapted to engulf pathogens and damaged tissue—and synthesising pro-inflammatory molecules, called cytokines (Terkawi et al., 2022). The synovial fluid is the most prominent site of inflammation (Sanchez-Lopez et al., 2022). Angiogenesis (the production of new blood vessels) near the cartilage of synovial joints is a hallmark of OA. Vascularising an area that typically does not have a high blood flow can cause swelling and allow for the infiltration of immune cells and cytokines into the joint area (Mapp & Walsh, 2012). Inflammatory cytokines, the main ones being IL-1β, TNF-α and IL-6 in OA, favour catabolic events in the joints. This involves increasing cartilage destruction through the activation of matrix metalloproteinases and acting on pathways that can suppress genes that reduce Type II collagen synthesis or express genes that stimulate chondrocyte death (Molnar et al., 2021).
The natural progression of inflammation involves a stage of repair. However, in the case of OA, the inflammation is chronic. Consequently, the ongoing inflammation can sensitise nerve endings in the joints so that pain sensation becomes heightened, even when there is no direct injury present (allodynia) (Mapp & Walsh, 2012). Additionally, ineffective attempts at repairing the damage can cause the formation of small bony outgrowths on the articulating bones, called osteophytes, which cause pain (Man & Mologhianu, 2014). The mainstream understanding of OA as a "wear and tear" condition due to ageing can be expanded upon by connecting ageing with inflammation. The phenomenon researchers refer to as "inflammageing" suggests that OA is prevalent in older individuals due to a constant inflammatory state that is observed in them (Motta et al., 2022). Not only are there elevations in inflammatory mediators in older people, but visceral fat in individuals with obesity also creates an inflammatory environment (Nedunchezhiyan et al., 2022). Hence, the existing inflammation, which can also be worsened by injuries, can disrupt the normal function of chondrocytes in the synovial joints and hence, prompt the development of OA.
Treatments of Osteoarthritis
What is currently available?
As advised by the National Health Service [NHS] (2019) there are three primary treatment options for OA. Losing weight and incorporating exercise into your daily life are lifestyle changes that can halt the degradation of synovial joint cartilage and inhibit inflammation. Analgesics (painkillers) and anti-inflammatory medication, such as non-steroidal anti-inflammatory drugs (NSAIDs), are used to target pain pathways to reduce joint pain. Finally, physiotherapy can be recommended for individuals with OA; it can help guide patients on how to keep active without further damaging the joints and can involve massages that ease the pain caused by the disease (NHS, 2019). However, all three treatment types have limitations. Patients with knee OA were asked to evaluate their experience of OA treatment in a qualitative study. Common responses included complaints about how OA medications can not sustain pain relief, have side effects and are not specialised to target the pathophysiological mechanisms of OA, like cartilage degradation. Lifestyle changes to treat OA have been found to be a frustrating treatment option for patients. There are multiple factors that may prevent a person from regularly exercising or losing weight, including upstream factors like socioeconomic status (inability to afford a healthy diet) and personal factors, for example, low motivation or a lack of time due to other commitments. Physiotherapy is similarly flawed as it may not be widely available to everyone suffering from OA and may not be personalised for each individual (Singh, 2021; Vitaloni et al., 2020).
Future of Osteoarthritis Research and Treatment
The search for how to improve the quality of life for people living with OA is limitless, with new research continuously evolving our understanding of the disease. Until recently, elucidation of OA pathophysiology was done in mice models of post-traumatic OA. To create an ageing-dependent OA model, researchers Suo and colleagues genetically modified mouse models so that they no longer expressed the ZMPSTE24 gene, the deficiency of which is associated with accelerated ageing. They found that when ZMPSTE24 was absent, mice were more likely to develop OA. This was because the loss of ZMPSTE24 disrupts the normal metabolism of chondrocytes and increases the methylation of a specific histone protein, causing chondrocyte senescence. As ZMPSTE24 expression naturally decreases with age, it can be a potential target in halting the progression of age-dependent OA (Suo et al., 2023). More studies are being conducted that explore the potential of reversing epigenetic changes implicated in OA. A specific enzyme, known as KDM2/7 histone demethylase, was shown to be significant in the pathophysiology of OA in mice. By inhibiting the demethylase, researchers were able to prevent an epigenetic change (demethylation) to a specific histone protein. This protected the joint from any further OA damage (Onuora, 2023). Hence, future treatment of OA may become preventative by targeting the pathways that induce epigenetic changes.
Current first-line treatments of OA are not equipped to target the pathophysiology of the disease. Although NSAIDs are used to combat the inflammatory aspect of the condition, the relief is temporary and the effects are not localised to the affected joints (Singh, 2021). Researcher Bolander and colleagues established a potential way to modulate the environment of the synovial fluid, changing it from an inflammatory state into an anti-inflammatory state to allow cartilage regeneration. They injected a co-culture of T cells (immune cell) with anti-inflammatory properties and mesenchymal stem cells (a cell type that has the power to differentiate into new chondrocytes) inside the joints of rat models and human OA patients. This prompted the local environment of the joint to re-establish homeostasis as the inflammation was inhibited by the injection of the co-culture, allowing for the repair and regeneration of damaged tissue. Therefore, modulating the environment of the joint by targeting inflammatory pathways can be another treatment option that will become available in the future (Bolander et al., 2023). Another method that recognises the need to focus on the main disease process of OA, which is cartilage degeneration, is the use of scaffold technology. A scaffold is a synthetic structure inserted into the joint that is designed to imitate the natural ECM of the cartilage and the underlying bone of a joint. This mimicry allows for the scaffold to be a structural point to which native chondrocytes and bone cells can attach and begin proliferating effectively, inducing a process of joint regeneration. These scaffolds can be multi-layered, deliver drugs that facilitate cartilage regeneration and contain cartilage cells within them to promote repair (Niu et al., 2023). A study performed in sheep, that had damage to the cartilage and underlying bone, showed noticeable improvements in the health of their joints six months after the insertion of the scaffold. This treatment option could halt the progression of OA and serve as an intermediate treatment – after trialing NSAIDs but before being referred to joint replacement surgery, which is done in late (or severe) OA (Tamaddon et al., 2020).
The incorporation of exercise into the lives of OA patients is strongly recommended but there is often a lack of specific advice regarding what physical activity is deemed ‘safe’. There is also an increasing tendency to lead a sedentary lifestyle (Kong et al., 2022). All this culminates in the need of ways that will promote beneficial lifestyle changes that can treat OA. Focusing on the effects of wearable devices, such as smart watches, has led researchers to believe that this can be a way to monitor activity in OA patients, even tracking the intensity of the physical activity and evaluating its effect on the affected joint (Ravalli et al., 2022). An ongoing research endeavour is also looking at delivering digital programmes to individuals with knee OA. The electronic programmes will either provide exercises for the patient to perform without any further direction or will be in the form of a video call with a group physiotherapist, with whom the patient can interact with (Groves-Williams et al., 2022). With this type of research being performed, there is hope that measures to assist OA patients in improving their lifestyles will be integrated into the healthcare system.
Case Study
A 46-year-old woman suffers from OA in her hip and hand joints. The onset of the disease began after the woman suffered an injury at eleven years of age. It is difficult to manage the joint pain as she has trialed 15 varieties of medications with only oxycodone, an opioid that acts as a pain killer, being moderately effective in easing joint pain. She has undergone hip replacement surgery but due to it being unsuccessful, she now has to use a wheelchair (Richardson et al., 2008).
From this case study, it is clear how OA can have a detrimental effect on a person’s life. Along with the physical repercussions of the disease, OA patients tend to suffer from mental health illnesses. The affliction of the joints, which can disable and limit a person’s actions, can lead to a loss of identity. Additionally, the lack of effective treatment options can become disheartening (Richardson et al., 2008; Vitaloni et al., 2020).
Conclusion
This article gave an overview of OA, one of the most common forms of arthritis. The pathophysiology of OA is complex, despite popular belief that it is a disease that afflicts older people who have experienced ‘wear and tear’ over time. OA causes cartilage degeneration and localised inflammation, yet current treatments typically involve lifestyle changes, physiotherapy and painkillers to address joint pain. To improve the quality of life of those who live with OA, therapeutics need to be designed to be preventative of OA, which will target epigenetic changes associated in the cause of OA and assist in repairing the damaged joint. Personalised advice and monitoring is also important to help OA patients take necessary steps to change their lifestyle in a way that will be beneficial for their health. The amount of research that goes into the elucidation of the processes involved in mediating OA opens up the possibility of a future with successful management, and a potential cure, for the disease.
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