Osteoarthritis (OA) is a chronic condition that affects the joints and results in abnormalities in the subchondral bone and cartilage and is one of the primary causes of disability (Peng et al., 2021; Zhong et al., 2022). The number of patients with OA-related disabilities increased by 114.5% globally between 1990 and 2019 (Long et al., 2022). According to the Centers of Disease Control and Prevention (Centers for Disease Control and Prevention, 2020), OA affects more than 32.5 million adults in the United States. Globally, around 240 million individuals have OA which limits their ability to engage in certain activities (Katz et al., 2021). Based on a review of 88 studies, females (1.69) had a higher incidence of OA than males (1.39) and the prevalence of OA rose with ageing and peaked between the ages of 70 and 79 (Cui et al., 2020). OA has been constantly on the rise in prevalence over the past 50 years as the life expectancy of people has increased (Mao et al., 2021). Moreover, it is expensive, contributing to an increase of $185.5 billion in healthcare costs between 1996 and 2005 which leads to a social and financial burden to the individual, healthcare system and society (Parmelee et al., 2015). According to data from the National Institutes of Health’s Osteoarthritis Initiative (OAI) study, those with multiple sites of OA, as well as hip or knee OA, are more likely to develop depressive symptoms (Veronese et al., 2017). Greater odds of memory loss and suicidal thoughts are found in OA patients, with these effects being primarily mediated by sleep deprivation and mood disorders brought on by joint pain (He et al., 2020). Some common symptoms of OA are pain, stiffness, popping or crepitus during joint motion, discomfort, swelling or even deformity of the joints, and mobility issues, particularly acute and fleeting morning stiffness (Fu et al., 2018).

Any joint throughout the body can develop OA, but it most commonly affects big weight-bearing joints like the knee and hip, which are characterized by reactive bone hyperplasia at the boundary of the joint and below the cartilage, thin and harsh articular cartilage, and synovial distension and inflammation (Litwic et al., 2013; Hunter and Bierma-Zeinstra, 2019). Numerous degenerative changes, including cartilage erosion and matrix breakdown, the production of pro-inflammatory mediators, chondrocyte death, and stimulation of macrophages in the synovium, developed as OA progressed (Hunter and Bierma-Zeinstra, 2019). Joint space narrowing, formation of osteophytes, subchondral sclerosis, cysts formation, and bone shape irregularities are all radiographic signs of OA (Arden and Nevitt, 2006). OA is a heterogeneous disease that affects all joint components including the ligaments, capsule, synovium, articular cartilage, and subchondral bone leading to tissue-level failure (Brandt et al., 2006; Varady and Grodzinsky, 2016; He et al., 2020). Among the degenerative changes, the degradation of cartilage is thought to be the essential characteristic of OA because articular cartilage is physically positioned in the forefront of the body’s response to the local biomechanical environment by offering a low friction system and precisely absorbing and distributing mechanical pressures imparted to the articular joint to facilitate mobility (Poole, 2012; Camarero-Espinosa et al., 2016).

There are various therapeutic strategies available for OA, such as exercise therapy, acupuncture, weight management, topical therapies, arthroscopic lavage and debridement, viscosupplementation, and pharmacological treatment using non-steroidal anti-inflammatory drugs (NSAIDs) (Lee et al., 2013; Cucchiarini et al., 2016; Luan et al., 2019; Tu et al., 2021). Yet, all the treatments are palliative and did not focus on treating or reversing the disease, and NSAIDs are chondrotoxicity and bring various side effects on organs such as the cardiovascular system, gastrointestinal system, and kidneys (Al Faqeh et al., 2012; Sukhikh et al., 2021; Shi et al., 2022). In the bargain, arthroplasties and osteotomy are still the sole approach to treating people with end-stage OA. However, this approach is intrusive and did not completely restore joint function (Xu K. et al., 2021; Mohd Yunus et al., 2022). Thus, a disease-modifying osteoarthritis drug (DMOAD) that can mitigate, halt, or reverse the development of OA is desperately needed (Hermann et al., 2018). The progression of OA does not only depend on a single cytokine alone. Instead, different cytokines can also stimulate the same signaling pathways, and the interaction between several variables is critical in the initiation and development of the disease (Molnar et al., 2021). Moreover, the direct etiology of OA is difficult to determine, but there are a few risk factors associated with OA, including ageing, genetic predisposition, obesity, trauma, inflammation, hormone profile, and excessive loading (Lee et al., 2013; Mohd Heikal et al., 2019; He et al., 2020). However, OA is known as a chronic, polygenic, and multifactorial joint condition associated with ageing (Man and Mologhianu, 2014). The possibility of developing OA greatly increase with age. During ageing, there will be change in the tissue’s mechanical and biochemical properties causing gradual buildup of damaged organelles and macromolecules in somatic cells which reduces the cells’ capacity for survival and proper function (Vellai, 2009; Peters et al., 2018). Also, the development of OA has been correlated with various proapoptotic factors that triggers apoptosis (Grogan and D’Lima, 2010). Therefore, therapies that can inhibit catabolic activities, promote anabolic activities and prevent chondrocytes death by targeting signaling pathways are the goals of OA therapies. In this study, the potential avenues for reducing chondrocyte apoptosis and the possibility of targeting apoptosis have been discussed to provide insight for targeting apoptosis in the treatment of OA.

There are different types of cell death that lead to OA. These include apoptosis, necrosis and chondroptosis (Salucci et al., 2022). Chondrocyte necrosis is generally less prevalent in OA as it is acute and normally occurred when tissues are exposed to severe mechanical injuries or highly toxic substances (Del Carlo and Loeser, 2008). On the other hand, chondroptosis, a non-classical manner of chondrocyte death occurs due to unusual chondrocytes condition to eliminate cellular remnants without inflammation such as hyperthermia (Salucci et al., 2022). For this study, our focus was on investigating cell apoptosis in the context of OA treatment (Heraud et al., 2000; Musumeci et al., 2011; Thomas et al., 2011; Zamli and Sharif, 2011; Lu et al., 2012).

Apoptosis or programmed cell death is a genetically determined cell removal process that is essential in various biological processes such as normal cell renewal, immune system development and operation, embryogenesis, chemical-induced apoptosis, and hormone-depending degeneration. Apoptosis is a normal process as well as a homeostatic mechanism that occurs during development and ageing to sustain cell populations in tissue. When there is an occurrence of immune reactions, disease, or toxic chemical-induced cell damage, it will act as a defensive mechanism (Chowdhury et al., 2006; Elmore, 2007). Cell apoptosis is normally characterized by the condensation of chromatin and disintegration of nuclear in the nucleus together with pyknosis, pseudopod retraction, and rounding up of the cell (Kroemer et al., 2009). Apoptosis dysregulation results in pathological conditions such as cancer, developmental abnormalities, and degenerative illnesses (Hwang and Kim, 2015).

Caspases, a group of cysteine-dependent aspartate-directed proteases are the main mediators of apoptosis through a sequence of chemical reactions (Palai and Mishra, 2015). The intrinsic (or mitochondrial pathway) and extrinsic (or death receptor pathway) pathways are the two most common apoptosis induction routes (Figure 1). Both paths finally result in a shared pathway or the apoptosis execution phase (O’Brien and Kirby, 2008). In the extrinsic apoptosis pathway, the receptors in the tumor necrosis factor (TNF) receptor superfamily such as Fas and/or TNF-related apoptosis-inducing ligand (TRAIL) receptors, TNF receptors (TNFR) and Fas (CD95) play an important role. All the receptors are characterized by a cysteine-rich extracellular domain and a cytosolic domain which together act as a death domain. The binding of extracellular apoptosis signal (Fas ligand, TRAIL, and TNF-α) to the death receptors causes the formation of a death-inducing signal complex (DISC) consisting of receptors and adaptor proteins such as Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD) that able to recruits and activate procaspase 8. Caspase-8 further activates caspase-3, resulting in cell apoptosis (Wong, 2011; Hwang and Kim, 2015).

Nevertheless, the intrinsic apoptosis pathway is activated by intracellular signaling including non-receptor-mediated stimuli that occur during failure to maintain survival signs such as the absence of hormones, growth factors, cytokines, and presence of the noxious stimuli such as toxins, hypoxic condition, radiation, and free radicals (Subasinghe et al., 2011). The crucial event in the intrinsic apoptosis pathway is mitochondrial outer membrane permeabilization (MOMP). The stimulus will cause permeabilization of the mitochondrial outer membrane permeabilization (MOMP), causing the release of intermembrane apoptotic and apoptotic molecules such as the second mitochondria-derived activator of caspase/direct IAP binding protein (Smac/DIABLO), serine protease Omi/high-temperature requirement protein A2 (HtRA2) and cytochrome c (cyt c) in mitochondria to the cytoplasm of the cell. During the activation of the intrinsic apoptosis pathway, the Bcl-2-associated X protein (Bax) and Bcl-2 antagonist killer 1 (Bak) proteins in cytosol will translocate to mitochondria, stimulating the release of cytochrome c (cyt c). The cyt c, together with adenosine triphosphate (ATP), apoptosis protease activating factor-1 (Apaf-1), and caspase-9 form apoptosome complex that in turn activates the executioner caspases pro-caspase-3 and 7, resulting in apoptosis (Kroemer et al., 2007; Howley and Fearnhead, 2008; Hwang and Kim, 2015). At the same time, the release of second mitochondria derived activator of caspase/direct IAP binding protein (Smac/DIABLO) and serine protease Omi/high-temperature requirement protein A2 (HtRA2) disrupts the binding of inhibitor of apoptosis protein (IAP) with caspase-9, caspase-3, and caspase-7 leading to the release and activation of executioner caspases (Schimmer, 2004; Wong, 2011). Both intrinsic and extrinsic apoptosis pathway activates caspase 3 that in charge of nuclear apoptosis through the activation of activated caspase-3 splices poly (ADP-ribose) polymerase (PARP) that inactivate PARP and subsequently cause cell apoptosis (D’Amelio et al., 2010). Consequently, the caspase in the downstream pathway promotes the cleavage of deoxyribonucleic acid (DNA) repair protein, cytoskeletal proteins, protein kinases, and endonucleases family inhibitory subunits. Together, they also affect the cell cycle, signaling pathways, and cytoskeleton leading to apoptosis (Ghobrial et al., 2005).

In this study, chondrocytes apoptosis has been selected as the target for DMOADs as apoptosis has been thoroughly investigated and has been extensively recognized as the most significant kind of cell death. Several studies have shown that OA patients’ articular cartilage contains more apoptotic chondrocytes as compared to healthy individuals (Heraud et al., 2000; Musumeci et al., 2011; Thomas et al., 2011; Zamli and Sharif, 2011). Furthermore, one of the crucial risk factors of OA is ageing. Apoptosis, a controlled form of cell death is particularly significant in the context of ageing-related events (Lu et al., 2012). Moreover, chondrocyte death is one of the central characteristics of the cartilage of the OA patients contributing to the loss of the cartilage matrix and decreased tissue (Zamli and Sharif, 2011). Articular cartilage is known to have low turnover of extracellular matrix and cells and various tests in mature cartilage revealed only a very small fraction of proliferating cells (Caramés et al., 2010). Besides, chondrocytes are the main and only occupant cells in articular cartilage, which are crucial for controlling extracellular matrix (ECM) synthesis and turnover as well as for preserving cartilage structure (Hwang and Kim, 2015; Varela-Eirin et al., 2018). As cartilage tissue is non-innervated, avascular and lacking the characteristics of undifferentiated cells, chondrocytes only possess weak self-repair capabilities after cartilage injury (Ude et al., 2014; Abramoff and Caldera, 2020; Ahmad et al., 2020). A net loss of chondrocytes results from an imbalance between the rate of death and proliferation or differentiation, compromises the homeostasis of cartilage (Grogan and D’Lima, 2010). Hence, the loss of chondrocytes in cartilage is believed to be the leading cause of the progression of OA. This strategy could assist in the management of OA and help mitigate the long-term effects of changes brought on by ageing.

There are various apoptosis mediators, such as reactive oxygen species (ROS), nitric oxide (NO), cytokines and mechanical stress available which can induce both cartilage degradation and apoptosis. In normal conditions, chondrocytes maintain a delicate equilibrium between the synthesis and breakdown of ECM components primarily collagen type II and proteoglycan (Hosseinzadeh et al., 2016). When OA progresses, there will be an overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β). This condition further promotes the secretion of proteolytic enzymes by chondrocytes, including matrix metalloproteinases (MMPs) as well as a disintegrin metalloproteinase with thrombospondin motifs (ADAMTs) which brings to the breakdown of key components in ECM (Wang et al., 2011). As the matrix constituent’s breakdown overrides the synthesis of the new matrix, the homeostatic balance is disrupted, shifting the homeostasis towards catabolism. At the same time, the inflammatory mediators will recruit leukocytes to the joints and result in the production of ROS, further promoting catabolism and causing chondrocytes death (Lee et al., 2013; Hosseinzadeh et al., 2016). The apoptosis of chondrocytes and ECM degradation may remain intact and form a destructive cycle, each exacerbating the other. The ability of chondrocytes to secrete ECM components will be reduced and causing difficulties in articular cartilage repair. The continuous loss of cartilage reduces the protective ability of cartilage to joints and further stimulates OA occurrence (Musumeci et al., 2014; Fu et al., 2018). Hence, chondrocyte apoptosis may be the target for the stop or reversing the development of OA. Although the caspase-mediated proteolytic cascade is the crucial mediators of apoptosis, the onset of apoptosis is tightly modulated by numerous factors such as TNF, p53 and Bcl-2 family proteins (Chowdhury et al., 2006). Therefore, this review aims to summarize the possible route in inhibiting chondrocyte apoptosis.

Table 1 below summarizes the studies that showed the abilities of various compounds to successfully inhibit cell apoptosis via activation or inhibition of signaling pathways. This provides endless possibilities for the discovery of novel OA treatment agents and proved that the chondrocytes apoptosis pathway could be one of the targets in the development of DMOAD.

A major element in the development of OA is the apoptosis of chondrocytes, which are the principal cells in charge of maintaining and repairing articular cartilage. The loss of chondrocytes impairs the ability of the remaining cells to sustain normal matrix production, which further degrades the cartilage matrix and accelerates the disease’s progression. A vicious loop that prolongs the disease is also created by the production of numerous pro-inflammatory chemicals by apoptotic cells, which can further promote cartilage breakdown and joint inflammation (Place and Kanneganti, 2019). Moreover, apoptotic cells may also cause the activation of immune cells such as macrophages, which can worsen joint inflammation and injury (Gordon and Plüddemann, 2018). As a result, creating therapeutic approaches that specifically target apoptosis is one of the key strategies for the treatment of OA.

Among various targets related to the apoptosis pathway, targeting the ER stress pathway is a promising therapeutic approach for the treatment of OA. This is because ER stress is stimulated by various stressors such as nutrient deprivation, oxidative stress, hypoxia and aging-related advanced glycation end products (AGEs) accumulation which are essential factors in causing progression of OA (Rellmann et al., 2021). Furthermore, ER stress is also an early phase in chondrocytes’ apoptosis process. Through targeting ER stress, cellular homeostasis can be restored and the effects of stressors in OA progression can be minimized. Overall, the ER stress pathway is a key regulator of apoptosis, and targeting this pathway holds great potential for treating various diseases, including OA.

Although there are various routes of administration of potential DMOADs to treat OA, intraarticular injection is recommended as the main therapeutic strategy due to several reasons including targeted distribution and better bioavailability (Jones et al., 2019). The articular cavity is less responsive to systemic medication delivery as it is avascular and innervated which limited the blood and oxygen supply (Zhang et al., 2022). Besides, the dense ECM due to organization of proteoglycans and collagen fibres of cartilage also hinders the effective delivery of drugs. Furthermore, the high concentration of negatively charged molecules consists in the ECM, makes the delivery of drug with negative charge even harder. These factors make most of the treatment modalities of OA challenging (Li et al., 2021). Also, through intraarticular injection, the therapeutics agents can be directly injected into the joint space which increases the concentration of drug to reach the pathological site as the treatment agents can bypass barriers such as liver metabolism and gastrointestinal tract. This approach helps to maximize the effectiveness of the drugs and at the same time minimize the systemic side effects (Evans et al., 2014; Emami et al., 2018).

OA is a heterogeneous disease with different phenotypes that can vary in terms of disease severity, clinical presentation, and underlying pathophysiology. Some of the common phenotypes of OA include senescent phenotype, inflammatory phenotype, metabolic phenotype, genetic phenotype and endocrine phenotype. These different phenotypes of OA may have distinct underlying mechanisms and may require different treatment approaches (Van Spil et al., 2019). However, there are various phenotypes of OA, the senescent, inflammatory, and metabolic phenotypes might be reversed by targeting chondrocyte apoptosis as the disease mechanisms involved in these phenotypes are tightly related to apoptosis of chondrocytes.

Targeting apoptosis in damaged chondrocytes is assumed to have therapeutic benefits without harming normal chondrocytes. This hypothesis is generated based on the different expression levels and activity of various apoptotic regulators between damaged and normal chondrocytes which increase the susceptibility of therapeutic compounds to damaged chondrocytes (Singh et al., 2019). Several compounds have been shown to alleviate and prevent chondrocyte apoptosis in preclinical studies, including natural compounds, antioxidants, drugs, and microRNA. The use of microRNA in OA treatment is one of the promising approaches. However, there are still many challenges such as biosafety issues, low in vivo efficacy, cytotoxic and high production cost (Holjencin and Jakymiw, 2022). Therefore, more efforts need to be done in future studies to make use of microRNA in treating diseases.

Currently, the field of apoptosis as a potential target is still in the preclinical stage as translating preclinical findings to a clinical setting is a complex and challenging task as there are countless factors such as safety concerns, optimization of dosage, selection of subjects, design of study and limited funding available. Hence, currently, the use of natural compounds is preferred as natural compounds are often easily accessible and cost-effective, it also has been proven to show osteoprotective and chondroprotective capabilities with fewer or no side effects (Pérez-Lozano et al., 2021). This makes them represent a promising avenue for the development of new therapeutic agents for the treatment of OA. However, more research is needed to fully understand the mechanisms of action of these natural compounds in chondrocyte apoptosis and OA progression and to determine their potential efficacy and safety in clinical settings.

In conclusion, this review recapitulated the possible targets for preventing chondrocyte apoptosis to alleviate the OA progression. In a nutshell, various mediators can stimulate chondrocyte apoptosis such as inflammation, oxidative stress, and ER stress. Several studies suggest that substances targeting mediators can be a potential DMOAD in halting or reversing OA progression. This study highlights the importance and potential targets that can be aimed at reducing chondrocyte apoptosis. In conclusion, this study could provide insights for researchers to further studies on OA treatment and management.