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1 Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations + 21321 word(s) 21321 2020-08-03 11:24:59 |
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Primorac, D.; Molnar, V.; Rod, E.; Jeleč, �.; Čukelj, F.; Matišić, V.; Vrdoljak, T.; Hudetz, D.; Hajsok, H.; Borić, I. Knee Osteoarthritis. Encyclopedia. Available online: (accessed on 18 April 2024).
Primorac D, Molnar V, Rod E, Jeleč �, Čukelj F, Matišić V, et al. Knee Osteoarthritis. Encyclopedia. Available at: Accessed April 18, 2024.
Primorac, Dragan, Vilim Molnar, Eduard Rod, Željko Jeleč, Fabijan Čukelj, Vid Matišić, Trpimir Vrdoljak, Damir Hudetz, Hana Hajsok, Igor Borić. "Knee Osteoarthritis" Encyclopedia, (accessed April 18, 2024).
Primorac, D., Molnar, V., Rod, E., Jeleč, �., Čukelj, F., Matišić, V., Vrdoljak, T., Hudetz, D., Hajsok, H., & Borić, I. (2020, August 07). Knee Osteoarthritis. In Encyclopedia.
Primorac, Dragan, et al. "Knee Osteoarthritis." Encyclopedia. Web. 07 August, 2020.
Knee Osteoarthritis

Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients.

knee osteoarthritis cytokines epigenomics platelet-rich plasma mesenchymal stem cells genetic therapy phenotype

1. Introduction

Osteoarthritis (OA) is the most common progressive musculoskeletal condition that can affect joints, but it mainly affects the hips and knees as predominant weight-bearing joints [1][2][3]. Knee osteoarthritis is characterized by structural modifications to primarily articular cartilage and the subchondral bone, but also Hoffa’s fat pad, synovia, ligaments and muscles, leading to the concept of observing OA as a whole joint disease [4][5][6][7].

Because of the higher prevalence of asymptomatic OA, it is approximated that 250 million people all over the world suffer from OA [8][9]. The prevalence of knee OA increased significantly over the last decades and continues to rise, partially because of the increasing prevalence of obesity and other risk factors, but also independently, of other causes [10]. It is estimated that the prevalence of knee OA among adults 60 years of age or older is approximately 10% in men and 13% in women [11]. According to GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, approximately 85% of the burden of osteoarthritis worldwide is connected with knee OA [12]. This is also seen by a rise in prevalence of knee OA of 32.7% from 2005 to 2015, making OA one of the leading causes of global years lived with disability (YLD) [12]. OA causes an annual economic burden of at least USD 89.1 billion—which is between 1% and 2.5% of the gross domestic product in high-income countries, with knee and hip joint replacements as the majority of that cost [9][12]. Furthermore, after low-back pain, osteoarthritis is the second leading musculoskeletal disorder in Disability Adjusted Life Years (DALYs) calculation in the elderly population [13].

Age, previous knee injuries, but also obesity (increased body mass index (BMI)), joint malalignment and instability that result in increased mechanical stress are all strong risk factors for the development of knee OA [14][15][16]. Repetitive actions, such as often kneeling and heavy lifting, together with professional sports activities, such as long-distance running, football, handball and hockey are associated with a higher risk of developing OA, due to more frequent injuries, causing cartilage defects, meniscal and anterior cruciate ligament (ACL) tears [17][18][19][20].

Physical inactivity is also another important contributor to the increasing prevalence of OA, causing higher susceptibility to knee damage due to less stable and weaker joints [20]. However, the weakness of knee extensor muscles seems to be a weak risk factor, compared to previous knee injuries [8].

Men are less likely to develop OA than women, making sex one of the risk factors associated with OA development [8]. Narrower femurs, thinner patellae, greater angles of quadriceps and differences in the size of tibial condyles make women’s knee anatomy different from men’s, leading to different kinematics, which influences female sex to be more likely to develop OA, ultimately leading to a higher prevalence of OA in women [21][22].

Studies have shown that there is a connection between OA and a slightly increased risk of developing cardiovascular and atherosclerosis-related diseases [23][24][25]. In addition, people with lower-limb OA are more likely to develop depressive symptoms due to chronic pain, as the most frequent and the most severe consequence of OA [16]. As a leading cause of depressive episodes, chronic pain causes a vicious cycle in which pain limits physical activity and physical inactivity contributes to greater knee pain and weight gain [16][20]. Unquestionably, OA is affecting people’s mental health and impacting the odds of suicidal ideas as well, which makes OA not just an economic, but also a major social, burden [16][26]. As a chronic disease with pain as the dominant symptom, pain management and lifestyle changes are insufficient, and OA remains challenging to treat. Joint replacement surgery is the only option left in end-stage disease to increase the quality of life in cases where conventional symptomatic treatment did not provide satisfactory results, making knee arthroplasty in OA as a revolutionary operation and a defeat of orthopedics, medicine and science at the same time [8]. However, secondary prevention and recent therapeutic measures including intra-articular applications of corticosteroid injections, hyaluronic acid injections, platelet-rich plasma (PRP) or autologous micro-fragmented adipose tissue with stromal vascular fraction may slow down the existing condition.

Genetics plays an important role in the pathogenesis of OA, as observed in 40% to 80% of the hip or hand OA, but significantly less in knee OA [8]. To date, 90 genetic risk loci for the development of OA have been identified using genome-wide association studies (GWAS) but a majority of those have low effect sizes [27]. Studies have shown that apart from the genetic risk loci, epigenetic mechanisms have a substantial impact on OA pathogenesis and progression [27][28]. Moreover, there are geographical and ethnic differences in OA prevalence. African-Americans are more likely to develop symptomatic knee OA in comparison to other races, whereas hip OA prevalence is low in Asian and Oriental populations [5][8].

Knowing that OA is a progressive condition, it is of great importance to assess for early signs of OA. This can be done by screening patient-reported outcomes, such as pain, function and quality of life, clinical findings such as joint tenderness and crepitus, objective measures of physical activity, and various imaging modalities, such as magnetic resonance imaging, along with biochemical markers [29].

The purpose of this review is to highlight recent studies of OA pathophysiology, imaging and state-of-the-art treatment methods, including research on prevalence, potential risk factors and future joint regeneration strategies. In this critical insight, we will endeavor to answer the majority of asked questions and provide up-to-date information on the topics mentioned above.

2. Pathogenesis and Histology—Osteoarthritis as a Whole Joint Disease

The approach to OA changed a lot throughout history. At first, it was thought that OA is a disease of cartilage. Later, the perception was replaced by an idea that subchondral bone is also affected, but today it is known that all the tissues in or around the joint are influenced by the disease, leading to the concept of OA as a whole joint disease.

2.1. Articular Cartilage

Articular cartilage (AC) is avascular, alymphatic, and aneural tissue with chondrocytes as the only cell type in the cartilage tissue [5][30][31]. Besides chondrocytes, AC is formed by the extracellular matrix (ECM), which is composed of water (more than 70%) and organic components such as type II collagen, aggrecan, other proteoglycans (decorin, biglycan, and fibromodulin), collagens (types III, VI, IX, XI, etc., collagens), glycosaminoglycans and glycoproteins [5][30][32]. Proteoglycan aggregates, built of negatively charged glycosaminoglycans (keratan sulfate and chondroitin sulfate) bound to the aggrecan core protein, that is linked with hyaluronic acid backbone, together with other matrix components, are entrapped in a network of cross-linked type II collagen fibrils, as portrayed in Figure 1 [31]. Premature termination codon on aggrecan mRNA affects cartilage development, while failure in aggrecan production may have a secondary effect on type II collagen, suggesting a possible extracellular matrix/type II collagen feedback regulation [33][34][35]. Although type II collagen and aggrecan are the most common proteins in the cartilage matrix, there is a distinct difference in the matrix structure around chondrocytes, where other proteins such as collagen VI, fibromodulin and matrilin 3 form the pericellular matrix [36]. All cartilage components are synthesized by chondrocytes, which play a key role in maintaining the cartilaginous environment by balancing the production of ECM components and its degrading enzymes, providing minimal and balanced turnover between anabolic and catabolic processes [37]. AC metabolism is stimulated by mechanical loading, detected by mechanoreceptors on the cell surface [38]. Through the process of mechanotransduction, mechanical signals modulate the biochemical activity of chondrocytes, inducing the biosynthesis of molecules to preserve the integrity of the tissue. Surface mechanoreceptors include mechanosensitive ion channels and integrins. Integrins are transmembrane proteins that activate internal cell signaling by binding chemical molecules, such as cytokines and growth factors [39]. The activation of these mechanoreceptors initiates intracellular signaling cascades, leading to the tissue remodeling process. Furthermore, biomechanical stimulus generated by dynamic compression during moderate exercise can reduce the synthesis of proteolytic enzymes, regulate the metabolic balance, and prevent the progression of cartilage damage [38]. The importance of proper mechanical loading is demonstrated by the fact that insufficient biomechanical stimuli, such as immobilization, can lead to reduced thickness (>10%) and softening of AC in the knee joint, in the absence of normal joint loading [40]. Conversely, excessive mechanical loading leads to a quantitative imbalance between anabolic and catabolic activity, resulting in the depletion of matrix components and, due to lack of AC regenerative capacity, leads to irreversible destruction, thus making it the most apparent triggering cause of OA [38].