Impact of Abnormal Mechanical Stress on Chondrocyte Death in Osteoarthritis

Introduction

Chronic degenerative arthritis of the knee, known as knee osteoarthritis (KOA), affects primarily middle-aged and older adults. Its pathological changes include thickening and degeneration of the joint capsule, secondary osteophytes, synovitis, subchondral bone changes, and spasms of the periarticular muscles [1]. The primary and most visible pathological sign of KOA is articular cartilage degeneration. The extracellular matrix (ECM) and chondrocytes that make up articular cartilage have the dual purpose of withstanding mechanical loads and fending off tensile and compressive stresses brought on by joint motions [2]. Knee cartilage has limited capacity for repair, due to the absence of blood vessels, nerves, and stem cells. Once its biomechanical qualities are compromised, it is particularly prone to KOA [2,3]. Articular cartilage loss and degeneration are accelerated by pathologic alterations in KOA that are linked to aging, obesity, genetic predisposition, overloading, trauma, metabolic syndrome, patient sex, and hormone levels [4]. Changes in the joint capsule and periarticular muscles can result from articular cartilage degeneration. This imbalance in the balance of joint biologic stresses can be caused by osteophytes, sclerosis of the subchondral bone outcropping, secondary synovial tissue inflammation, and other conditions. These lesions can also exacerbate KOA lesions by promoting more articular cartilage damage and degeneration [5,6]. Thus, one of the key mechanisms in the development of KOA is cartilage deterioration brought on by a dysregulation of the physiologic stress balance.

As one of the main risk factors for KOA at this time is inappropriate mechanical loading, it is crucial to investigate how mechanical stimulation affects chondrocytes, to better understand the disease’s pathophysiology and develop effective clinical interventions. On one hand, a profound understanding among medical professionals of the mechanism underlying KOA induced by abnormal mechanical pressure can effectively guide patients to perform appropriate functional exercises, thereby preventing abnormal joint damage. This not only helps in the management of existing conditions but also serves as a preventive measure against further deterioration. On the other hand, patients armed with a basic understanding of these mechanisms can proactively refrain from engaging in improper exercises, minimizing the risk of knee injury. This self-awareness empowers patients to take an active role in their own healthcare. Overall, promoting the understanding of the impact of abnormal mechanical pressure on the knee joint among doctors and patients can significantly alleviate the medical burden in China. This, in turn, holds great significance for enhancing overall national health and well-being [7].

The dispersal and absorption of mechanical loads are made possible by the novel nature of synovial joints. Distinct mechanical loads with distinct stress patterns have different effects on cartilage health depending on their severity, frequency, and duration [8]. For chondrocytes to preserve a homeostatic equilibrium between catabolic and anabolic processes, they require a moderate mechanical input. Furthermore, by controlling mechanisms linked to proliferation, such as triggering the release of growth factors or the transfer of latent transforming growth factor to its active form, moderate mechanical loading can encourage chondrocyte development and cartilage production. On the other hand, overload and repeated misuse of the joints can cause this equilibrium to be shifted to catabolic processes, which can result in osteoarthritis flare-ups and cartilage deterioration [9].

The physiology or pathophysiology of articular cartilage or other joint tissues can be altered by mechanical stress through intricate interactions with genetic and molecular effects, especially in the case of localized or systemic inflammation brought on by injury or obesity. It has been documented that mechanical loading can trigger a number of inflammatory pathways, including Wnt, microRNA, oxidative stress, tumor necrosis factor (TNF)-α, nuclear factor (NF-κB), and interleukin (IL)-1β, as well as their downstream signaling channels. By activating important articular cartilage degradative enzymes like metalloproteinases (MMPs) and aggregases (ADAMTs), these pathways contribute to the regulation of joint inflammation. These enzymes cause chondrocyte apoptosis, ECM degradation, subchondral bone dysfunction, and synovial inflammation, which ultimately results in KOA [10]. The aim of this article is to clarify the classification of abnormal mechanical loads and elucidate the distinct effects exerted by different stresses on chondrocytes. Ultimately, it endeavors to expound the molecular mechanisms underlying the microenvironmental changes in KOA induced by abnormal mechanical pressure.

As a result, this study examines the effects of various mechanical stress patterns on cartilage healing as well as the processes by which chondrocytes translate mechanical information into chemical signals that are carried inside their cells. It also studies the function of these molecular pathways in osteoarthritis pathophysiology and cartilage homeostasis, clarifying how mechanical loading influences the pathogenesis of osteoarthritis through molecular signaling pathways.

Material and Methods

In this study, a comprehensive review and analysis of relevant domestic and international literature were conducted to summarize the pertinent findings. The research time frame was set from January 1, 2014, to December 31, 2024, spanning nearly a decade. Data sources included renowned foreign-language databases such as PUBMED, Web of Science, and Google Academic. The types of articles considered encompassed original research works, review articles, systematic analyses, and relevant medical record reports.

The search strategy was 2-fold: First, Medical Subject Headings (MESH) were searched using terms “osteoarthritis”, “knee”, “mitochondrial diseases”, “ferroptosis”. Another medical keyword search was done with “knee osteoarthritis”, “mechanical pressure”, “mitophagy”, and “ferroptosis:. Finally, for the screening process, 2 scholars independently reviewed the literature. Irrelevant articles were meticulously screened out based on keywords and subject headings, ensuring the inclusion of only highly relevant and high-quality studies for further analysis.

Results

Role of Different Stress Patterns of Mechanical Stimulation on Cartilage Repair

ROLE OF DIFFERENT STRESS PATTERNS OF MECHANICAL STIMULATION ON CARTILAGE REPAIR:

Articular cartilage, which covers the surface of the bones in the joints, is one of the mechanically sensitive tissues of the human body and is constantly subjected to mechanical stimuli, with different stress patterns. Chondrocytes, as the only cells in the cartilage tissue, produce effects under mechanical stimulation. Currently, the main stress modes of mechanical stimulation include compressive stress, tensile stress, vibration, electromagnetic stimulation, and fluid shear. The response of chondrocytes to mechanical stimuli is highly selective; for example, dynamic hydrostatic pressure and direct compression at physiological loads and frequencies can stimulate cell regeneration and metabolism; however, abnormal mechanical stimuli, such as static compression, stretching, and injurious compression, can also lead to cartilage decomposition and metabolic changes. Therefore, it is important to understand the effects of different stress patterns of mechanical stimulation on cartilage repair.

EFFECTS OF COMPRESSIVE STRESS ON CHONDROCYTES: Static stress and dynamic stress are the 2 main types of compressive stress. Dynamic stress is more complicated, since it typically involves an ongoing, irregular pressure input, as opposed to static stress, which is the application of steady pressure to tissues or cells. It has been demonstrated that moderately prolonged and intense compressive stress stimulation can both promote the expression of proteoglycans and MMP-13 in the family of MMPs in chondrocytes and inhibit the expression of MMP-13 in MMPs. These changes affect the metabolic state of chondrocytes by adjusting the amounts of MMPs, COL-II, and proteoglycans [11–13]. Under these circumstances, compressive stress were also shown to aid in improving the phenotypic dedifferentiation of chondrocytes; however, chronic stimulation of compressive stress had adverse effects. By creating traction on the periphery through the cytoskeleton or by causing cytoskeletal breakdown that results in the reorganization of actin and wave proteins, compressive stress stimulation can cause changes in chondrocyte shape [14,15].

Articular cartilage has a compression modulus between 0.4 and 2.0 MPa under healthy conditions. Direct compression force deforms chondrocytes and modifies their intracellular Ca2+ content. Direct mechanical activation of Ca2+-dependent channels and indirect changes in membrane potential are maintained through voltage-manipulated calcium channels. Direct compressive stress promotes chondrocyte proliferation and raises the mRNA expression of ACAN and COL-II. Through a transduction process involving the activation of phosphatidylinositol and cyclic adenosine monophosphate (cAMP) signaling cascades, direct compressive stress generates higher mRNA levels of ACAN [16]. The cAMP and phosphatidylinositol pathways share common downstream mediators in direct compressive force-induced signaling. One mechanism of signal transduction is selective activation by compressive stress, resulting in downstream phosphorylation of key enzymes and mediators. Another mechanism is that signals generated by short-term compressive stress are transduced to the nucleus through the cAMP and phosphatidylinositol pathways in parallel, resulting in a synergistic activation of ACAN mRNA transcription [16] (Figure 1).

It was demonstrated that cyclic mechanical stress in the pressure range of 0 to 0.2 MPa and frequency range of 0.1 Hz greatly enhanced chondrocyte proliferation and matrix production, and this was linked to increased levels of phosphorylation of Src, PLCγ1, MEK1/2, and ERK1/2. The chondrogenic master gene SOX9, as well as the genes ACAN and COL-II, were all enhanced by cyclic dynamic compression [17].

EFFECTS OF HYDROSTATIC PRESSURE ON CHONDROCYTES: One of the main reasons articular cartilage can tolerate high-intensity joint loading is that hydrostatic pressure gives the surface of the cartilage on the knee limited coefficient of friction, allowing for minimal deformation of the knee joint and alterations in the cellular morphology [18]. The hydrostatic pressure level of chondrocytes in the joints under daily activities is 0.1 to 20.0 MPa, as demonstrated by scientific experiments [19]. The effects of hydrostatic pressure applied in vitro on articular cartilage matrix metabolism have been demonstrated by experimental investigations. In contrast to normal chondrocytes, KOA chondrocytes exhibited a higher percentage of marginal chromatin, morphological indications of cellular damage, and fewer mitochondria and Golgi bodies [20].

Hydrostatic pressure had no influence on type I collagen expression, but it could control chondrocyte metabolism through the Wnt/β-catenin pathway, boost the expression of COL-II and Bcl-2, and enhance the expression of Sox9, a crucial transcription factor for cartilage development. An application of 10 MPa overload hydrostatic pressure resulted in enhanced expression of mir-146a and mir-181a. The notable alterations in miRNA expression brought about by hydrostatic pressure in human chondrocytes imply that miRNAs can act as mechanical loading mediators to control chondrocyte metabolism. The main mechanism of hydrostatic pressure may be to promote cell proliferation and ECM production, which is consistent with previous studies reporting that hydrostatic pressure can regulate key signaling pathways and stimulate the secretion of growth factors, thereby promoting cell proliferation and ECM production [21]. It is hypothesized that hydrostatic pressure can contribute to improved internal cartilage formation by increasing diffusion pressure to promote material exchange, which may be an important reason why cartilage thickness was significantly higher in the hydrostatic pressure group than in other groups [22]. Future biomechanical research on cartilage restoration may focus heavily on the processes by which chondrocytes sense changes in ambient stress. Further investigation is required to determine the optimal loading conditions for stimulating chondrocyte metabolism to promote cartilage repair, as well as to assess how mechanical activation of TRPV1 versus thermal or pH activation induces different cellular signaling pathways, the negative regulation of the ERK pathway in chondrocytes, and the expression of SOX9 mRNA. Additionally, the signaling cascade pathway is activated by hydrostatic pressure (Figure 2).

ROLE OF SHEAR ON CHONDROCYTES: High fluid shear stress can cause inflammation, cell death, and cartilage deterioration; low fluid shear stress protects cartilage. In human arthritic chondrocytes generated by resistin, low shear stress can control the production of COX-2 by blocking the adenosine monophosphate activated protein kinase (AMPK)/deacetylase-1 (SIRT1) pathway [23]. Moreover, low shear stress can decrease the amount of NF-κB brought on by IL-1β, protect cartilage, and activate the transcription factor Kruppel-like factor 4. Peroxisome proliferator activated receptor γ can also be increased transcriptionally through ERK5 [23]. Resistin levels in serum and synovial fluid were found to be positively correlated with KOA severity [23]. It was discovered that via suppressing NF-κB and cyclic phosphoramidonate effector binding protein, modest shear force (2 dyn/cm2) applied to human arthritic chondrocytes for a brief duration reduced the effect of resistin on COX-2 production. Extended (3–4 h) shear, on the other hand, boosted NF-κB transcriptional activity, amplifying resistin’s effect on COX-2 production. It is possible that the primary transcription factor acting downstream of low shear to regulate COX-2 production in resistin-stimulated human arthritic chondrocytes is NF-κB. Furthermore, by upregulating the expression of the AMP-activated AMPK/SIRT1 pathway, resistin-stimulated COX-2 production was regulated by both shear modes. After applying high fluid shear (20 dyn/cm2) to human chondrocytes for 48 h, Guan et al observed that MMP1 expression was dramatically elevated, along with upregulated levels of COX-2, IL1β, and fibroblast growth factor-2 [24]. When combined, shear forces of varying lengths and intensities might be able to modulate variations in chondrocyte function and signaling, which would then affect cartilage metabolic balance (Figure 3).

EFFECT OF MECHANICAL LOADING ON CARTILAGE METABOLISM:

Numerous stressors encountered in daily living, such as compressive, tensile, and hydrodynamic (shear) forces, stimulate articular cartilage by activating several mechanosensitive proteins and collagen macromolecules, which in turn affect chondrocyte metabolism. While the peak load during exercise can reach up to 18 MPa, the knee joint’s loading range during regular activities is 5 to 8 MPa [25]. The mechanical properties of proteoglycans in the extracellular matrix play an important role in the ability of articular cartilage to carry these loads. When articular cartilage carries a certain load, the water adsorbed by the highly hydrophilic proteoglycan will be squeezed and released to cushion the external force and slow down the friction, so that the cartilage will have a certain degree of elasticity when under pressure [26]. Conversely, when the load is removed, the intertissue fluid flows back into the extracellular interstitium, such as proteoglycan, returning the cartilage to its original state. Thus, articular cartilage has certain mechanical properties and the ability to carry compressive forces. Appropriate mechanical loading stimulates the synthesis of ECM in cartilage [27]. On the other hand, the ECM can rapidly degrade in response to either an excessively low or large load. Patients with KOA frequently experience abnormalities in the metabolism of cartilage, articular cartilage degradation, and subchondral osteosclerosis as a result of excess body mass or a concentration of intra-articular stresses brought on by joint deformity. Additionally, patients who have experienced limb-wasting fractures or prolonged bed rest frequently experience metabolic abnormalities and thinning of the cartilage [28]. Consequently, the endochondral environment is negatively impacted by mechanical loads that are either too high or too low, and proper loading is a necessary condition for controlling cartilage formation, preserving cartilage integrity, and preserving subchondral bone function.

EFFECT OF LOW MECHANICAL LOADING ON CARTILAGE METABOLISM: Research has indicated that after a year, the thickness of cartilage decreases in persons with paraplegia by 9% to 13%. After an ankle fracture, lower extremity immobilization can also cause a noticeable reduction in the cartilage of the injured knee joint [29, 30]. Insufficient mechanical stimulation causes the cartilage in the knee to weaken and become more vulnerable to injury from collagen, which ultimately results in cartilage degeneration. Following knee breakage, articular cartilage contains higher levels of matrix metalloproteinases MMP-1 and MMP-3, with MMP-3 also encouraging a rise in ADAMTS5 [31,32]. A chondrocyte proteoglycan antibody called ADAMTS5 is crucial to the development of osteoarthritis. Research has indicated that decreased expression of the CBP/p300-binding translational activator Glu/Asp-rich carboxy-terminal domain 2 (CITED2) protein in chondrocytes in the absence of stress stimulation is one of the possible pathways for increased MMP and ADAMTS content in chondrocytes [9,32]. CITED2 prevents cartilage matrix from being degraded by MMP; however, in the absence of stress stimulation, CITED2 synthesis decreases, which leads to an increase in MMP synthesis and degradation of the cartilage matrix [9]. Another potential mechanism is, that in the absence of stress stimulation, the levels of IL-4 or IL-10 are increased in chondrocytes, which leads to an increase in the expression of the NF-κB signaling pathway, which further induces the catabolic effect of MMP on cartilage.

EFFECT OF MECHANICAL LOAD OVERLOAD ON CARTILAGE METABOLISM: Mechanical loading has a significant role in the etiology and development of KOA by exacerbating cartilage degradation. Three phases can be distinguished in cartilage injury resulting from mechanical overload: softening of the cartilage without loss of collagen, collagen loss without obvious damage to the cartilage, and, lastly, evident damage to the cartilage [33]. It has been found that knee overload caused by running leads first to a decrease in the glycosaminoglycan content of articular cartilage, cartilage softening, and subchondral bone remodeling. This subsequently leads to shallow cartilage tide lines, thinning of cartilage, and, ultimately, destruction of the extracellular collagen-like matrix of knee cartilage, resulting in irreversible cartilage damage [34]. Overloading can lead to the destruction of the ECM of cartilage, which promotes the formation of fibronectin, which activates integrins and Toll-like receptors (TLR2 and TLR4), followed by the activation of the MAPK pathway, and ultimately stimulates the breakdown of metabolized cartilage by NF-κB. NF-κB signaling is closely related to the secretion of inflammatory factors by knee chondrocytes and synoviocytes, which generates inflammatory responses. NF-κB signaling is closely associated with the secretion of various inflammatory factors by knee chondrocytes and synoviocytes, to produce inflammatory responses [35,36].

PIEZO electric mechanosensory ion channel assemblies that can be directly activated by mechanical loading to inward Ca2+ flow include PIEZO1 and PIEZO2 [37]. Application of PIEZO channel antagonists could decrease the extracellular Ca2+ in-flow and protect chondrocytes. It was discovered that PIEZO1 and PIEZO2 were stably expressed in chondrocytes and could mediate the transient Ca2+ in-flow under rapid mechanical stimulation. There was a significant increase in apoptosis in the treated area, and a large amount of Ca2+ in-flow in the chondrocytes treated with a high degree of mechanical loading [38]. Subsequent research showed that PIEZO1 expression was upregulated in OA cartilage following IL-1α activation, which further enhanced chondrocyte mechanosensitivity and increased their vulnerability to mechanical damage. PIEZO2, a force-sensitive ion channel protein found on chondrocyte membranes, has been linked to the deterioration of cartilage in situations involving significant tensile stress. It was discovered that PIEZO2 caused an increased influx of Ca2+ into chondrocytes under severe tensile stress, which resulted in cartilage matrix breakdown [39]. The transient receptor potential vanilloid subtype (TRPV) is a class of highly Ca2+-selective ion channels, which includes TRPV1 to TRPV6, of which TRPV4 mediates the signaling of mechanical loading under physiological conditions. Excessive mechanical loading can induce chondrocyte apoptosis by increasing Ca2+ inward flow through TRPV4. Excessive mechanical stimulation not only causes TRPV4 to activate NF-κB, promote MMP expression, and induce cartilage ECM degradation, but also induces large amounts of Ca2+influx, promotes the expression of caspase 3, caspase 6, and caspase 8, and induces chondrocyte apoptosis [40,41]. Both of the aforementioned calcium channel classes have similar but different functions. TRPV channels are more likely to be involved in long-term and extensive mechanical load transduction, such as prolonged high-load changes in the intra-articular environment, whereas PIEZOs are more sensitive and more likely to be initiated in response to mechanical load excitations, with a greater role in trauma.

MECHANICAL STRESS AND CHONDROCYTE APOPTOSIS: One important metabolic pathway that is tightly controlled in the adult body is apoptosis, which is essential for preserving the homeostasis of different tissues. Chromatin condensation, DNA fragmentation, cell shrinkage, plasma membrane blistering, and the development of apoptotic vesicles are all signs of apoptosis in cells. Human physiology has 2 primary mechanisms to cause apoptosis, which results in the activation of cysteine asparaginase (caspases). These pathways are extrinsic apoptotic receptor-mediated and intrinsic mitochondria-dependent [42]. After tissue damage, a range of cells, such as macrophages, lymphocytes, and neutrophils, gather at the site to start tissue repair. When the healing process is finished, any extra cells are removed by means of programmed cell death, to avoid excessive inflammation and subsequent tissue damage [43].

The inflammatory response and chondrocyte death are significant pathogenetic processes of KOA, the most prevalent chronic arthritis in the elderly. Inflammatory mediators, such as IL-1β, TNF, and nitric oxide, are released during chondrocyte degeneration. These mediators work through mitochondria-dependent mechanisms to suppress the synthesis of cartilage matrix, boost MMP activity, and upregulate the expression of pro-inflammatory cytokines that are involved in the breakdown of cartilage ECM [44]. STING expression was significantly increased in human and mouse KOA chondrocyte tissues exposed to IL-1β, and increased STING expression induced apoptosis by inducing ECM degradation [44]. It has been noted that mechanical tensile stress controls the process of apoptosis in growth plate chondrocytes. While excessive tensile stress can limit cell proliferation and differentiation and possibly even induce apoptosis, appropriate tensile stress can successfully stimulate cell proliferation and differentiation [45]. Additionally, it has been discovered that, whereas extreme mechanical stress causes severe mitochondrial malfunction and death, moderate mechanical stress prevents IL-1β-induced apoptosis by preserving mitochondrial activity and scavenging reactive oxygen species [46]. In a different investigation, scientists discovered that the estrogen pathway contributes to PIEZO1-mediated mechanical signaling in chondrocytes and that apoptosis in chondrocytes caused by mechanical stress is largely dependent on the activation of G protein-coupled estrogen receptors, not estrogen receptors [47]. In summary, this work discovered that PIEZO1 is inhibited by the G protein-coupled estrogen receptor, which attenuates mechanical stress-mediated chondrocyte death in osteoarthritis.

It is now thought that mechanical stress affects several molecular pathways involved in the development of osteoarthritis. Osteoarthritis is caused by overload because it triggers downstream molecular processes such as oxidative stress, TNF-α, IL-1β, and NF-κB pathways. These pathways also cause chondrocyte apoptosis and ECM breakdown [48]. However, it is worth noting that mechanical loading does not always have deleterious effects on articular cartilage. In fact, physiologic mechanical loading can activate the transforming growth factor-β pathway to protect cartilage. A number of receptors can detect mechanical signals in articular cartilage, including integrins, ion channel receptors, and TRPV-4 [49]. These molecular pathways offer prospective targets for osteoarthritis treatment and therapeutic prevention of mechanical load-induced osteoarthritis (Figure 4).

MECHANICAL STRESS AND MITOCHONDRIAL AUTOPHAGY IN CHONDROCYTES: Autophagy is a major catabolic process in eukaryotic cells that degrades and recycles damaged macromolecules and organelles. In cartilage homeostasis, its activation has been reported to reduce KOA severity. Many studies suggest that endoplasmic reticulum stress and autophagy are involved in mineralization and bone homeostasis. During the progression of cell injury or apoptosis, it has been found that knee joint loading regulates the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway [50]. In a further study, mechanical loading was found to increase phosphorylation of eukaryotic translation initiation factor 2α and regulate the expression of autophagy markers LC3II/I and p62. In one study, osteoarthritic mice also exhibited an elevated ratio of calcified cartilage to total articular cartilage and were found to have increased synovial hyperplasia and lining cells. In conclusion, this study found that mechanical loading reduces osteoarthritis symptoms by modulating endoplasmic reticulum stress and autophagy [50].

Mechanosensitive ion channels are an additional set of force sensors and regulators in chondrocyte mechanotransduction, and mechanical loading plays a complex and varied function in controlling chondrocyte signaling pathways. Mechanical stimuli cause these transmembrane protein channels to open quickly, causing a localized flow of ions across the membrane [51]. Cyclic compression results in decreased ATP synthesis and ATP/ADP ratios, as well as increased proton leakage, decreased mitochondrial membrane potential, increased reactive oxygen species creation, and suppression of respiratory activity. Chondrocytes are significantly impacted by these modifications. For instance, PTEN-induced putative kinase protein 1 (PINK1), which is typically imported into healthy mitochondria and destroyed by mitochondrial proteases, accumulates on the mitochondrial surface as a result of mitochondrial damage and depolarization [52]. If the input process fails due to mitochondrial dysfunction, PINK1 autophosphorylates, dimerizes, accumulates on the mitochondrial outer membrane, and then phosphorylates parkin and ubiquitin to trigger mitochondrial autophagy [53]. We think there is a causal link between mitochondrial dysfunction and the pathophysiology of OA because of the impact of mechanical stress on mitochondrial ATP synthesis, changes in membrane potential, and increased production and release of cathepsin. Furthermore, by impairing chondrocyte anabolic responses, this oxidation-dependent mitochondrial dysfunction brought on by mechanical stressors may be a factor in cartilage degradation across all phases of KOA. In response to mechanical stress, mitochondria absorb Ca2+, which is then released from the endoplasmic reticulum and enters the cytoplasm via lanyl alkaloid receptors to preserve cellular Ca2+ homeostasis. Extra calcium that builds up in the mitochondrial matrix causes a permeability transition pore to develop. This, in turn, causes the transmembrane potential of the mitochondria to break down, releasing calcium and mitochondrial proteins. The loss of mitochondrial proteins and subsequent depolarization of the mitochondria set off a chain of events that together form positive feedback regulation and ultimately result in cysteine-9-dependent apoptosis and cartilage breakdown [54] (Figure 4).

MECHANICAL STRESS AND CHONDROCYTE FERROPTOSIS: Mechanical stimulation is closely related to traumatic events of various cell types. During the occurrence and development of osteoarthritis, excessive mechanical load on chondrocytes can lead to enhanced catabolic reactions and excessive cell death [55]. On one hand, excessive mechanical stress promotes the expression of matrix degrading enzymes such as MMP-13 and ADAMTS-5 in chondrocytes, exacerbating the degradation of type 2 collagen and glycoproteins in cartilage tissue, causing softening and degeneration of cartilage tissue, and further reducing its ability to resist mechanical stress. On the other hand, excessive mechanical stress can induce the death of chondrocytes. As chondrocytes are the only cells that synthesize cartilage tissue, when a large number of chondrocytes die, the cartilage cannot be repaired in a timely manner, leading to further aggravation of the original damage and ultimately triggering the occurrence of osteoarthritis.

Cell death, especially programmed cell death, is closely related to tissue and organ degeneration, with ferroptosis playing a key role. Ferroptosis is a newly discovered form of cell death found in recent years to be characterized by phospholipid oxidative damage. This is a completely new way of cell death, different from necrosis, apoptosis, and autophagy. Cellular iron death is caused by oxidative damage that is dependent on iron ions and is characterized by wrinkled mitochondria and elevated lipid reactive oxygen species. The iron ion that regulates iron death the most is phospholipid hydroperoxide reductase-glutathione peroxidase 4 (GPX4) [56]. Finding new regulatory mechanisms for osteoarthritis and investigating the role of ferroptosis, a novel form of cell death, in the etiology of the disease are highly significant both theoretically and practically for the advancement of osteoarthritis treatment options [57].

It has been established that chondrocyte ferroptosis plays a role in the onset of osteoarthritis. By preventing chondrocyte iron death, osteoarthritis can progress more slowly, encourage cartilage anabolism, and prevent catabolism [56]. Numerous mechanical stress-induced cell viability change events have been linked to PIEZOl proteins. Previous investigations have indicated that when chondrocytes are stimulated mechanically, PIEZOl proteins cause metabolic problems. PIEZOl protein activation was discovered to be strongly associated with chondrocyte iron mortality. PIEZOl activation was associated with lower glutathione GSH levels, decreased expression of GPX4, and structural and functional damage of the mitochondria. Additionally, it was discovered that GPX4 might be a crucial downstream target of PIEZOl protein in chondrocytes experiencing mechanical stress-induced iron death [56].

Discussion

As a degenerative joint disease, KOA is extremely painful and inconvenient for patients. Because of its high incidence, it also places a significant financial strain on families and society [1]. The effects of either too much or too little mechanical loading on cartilage can lead to KOA progression; therefore, maintaining moderate mechanical loading is beneficial to cartilage health and slows disease progression [5].

In this study, we used 3 foreign language databases, with a high number of papers in the search results. Also, having the time set for the last 10 years has research significance and era significance. Furthermore, the 3 databases are currently the main article publishing addresses in natural science and are therefore of scientific interest. However, the amount of data we retrieved was too large, which had a certain impact on the results. In general, the search technology based on the 3 databases met the requirements. Through a variety of signaling pathways and molecular mechanisms, the mechanical pressure carried in articular cartilage can be converted into chemical stimulation in a variety of in vivo and in vitro mechanical experiments. This can lead to an increase in the expression of COL-2 and ACAN, a decrease in the expression of inflammatory cytokines, and an inhibition of the degradation of the ECM, all of which can contribute to cartilage protection [12,28]. However, further research is needed to fully understand the effects of each factor, as well as the signaling pathways and molecular mechanisms by which physical stimuli are transformed into chemical stimuli. Different types of mechanical stress, force loading duration, and frequency all have a significant effect on chondrocyte response to mechanical stimuli. The target sites and regulatory mechanisms of many mechanical responses remain unknown, and research on how mechanical loading affects cartilage repair is still in its early stages. Future biomechanical research on cartilage repair may focus heavily on understanding the mechanism by which chondrocytes sense changes in environmental stress. This will help to better understand chondrocyte mechanotransduction and the function of mechanical stress in tissue engineering and cartilage repair [45].

The original cartilage homeostasis is disrupted by age, mechanical stress, and inflammatory stimuli, which can lead to energetic disturbances, abnormal hypertrophy, and even chondrocyte apoptosis. This can also cause a high expression of related degradative enzymes that break down collagen and prevent chondrocytes from synthesizing ECM. When combined, these modifications cause an imbalance between the synthesis and breakdown of cartilage, which eventually results in the development of KOA cartilage degeneration. The process’s molecular basis is extremely intricate, involving a number of signaling pathways and cell death mechanisms that cooperate to control the growth of KOA and induce cartilage degradation [51]. While high mechanical stress causes acute mitochondrial malfunction and death, moderate mechanical stress preserves mitochondrial activity and scavenges reactive oxygen species to minimize IL-1β-induced apoptosis. Additionally, by blocking PIEZOl, the G protein-coupled estrogen receptor in osteoarthritis reduces the amount of chondrocyte death triggered by mechanical stress [42]. Oxidation-dependent mitochondrial dysfunction induced by mechanical stimuli may lead to cartilage destruction at all stages of OA by disrupting chondrocyte anabolic responses [14,43]. The chondrocytes experienced a reduction in intracellular glutathione GSH levels, a decrease in GPX4 function and expression, and a significant increase in calcium ions after the PIEZO1 protein was activated during high mechanical stress stimulation. This ultimately led to chondrocyte iron death, which was characterized by increased oxidative stress, mitochondrial structural and functional dysfunction, chondrocyte synthesis, and catabolic imbalance. Furthermore, in chondrocytes subjected to high mechanical loads, further supplementation with the iron death bypass regulators Fspl and coenzyme Q10 can aid to mitigate iron death and oxidative damage [38, 39]. All things considered, the activation of the PIEZO1 protein in response to mechanical stimulation is crucial for the processes of apoptosis, autophagy, and iron death. Consequently, it is crucial to conduct additional research on the several biochemical pathways that follow PIEZO1 activation in response to mechanical stimulation.

Thanks to advice we received, we will supplement future guidance and suggestions in the manuscript. Currently, there is a lack of therapeutic drugs capable of effectively halting the progression of KOA. Identifying novel therapeutic targets for KOA and translating them into clinical applications remains a primary objective for a majority of researchers.

Consequently, for clinicians, a promising future research focus could be on the differential effects of various mechanical pressures on KOA. It will be of great significance to invent or develop interventions that mitigate the effect of different activities on patients’ joints. This can be achieved by delving into the role of distinct mechanical stimulation stress patterns in cartilage repair and the mechanisms through which chondrocytes transduce force signals into intracellular chemical signals. Furthermore, a more in-depth exploration of the molecular mechanisms by which mechanical load influences chondrocyte death via molecular signaling pathways not only offers new strategies for the diagnosis of KOA but also paves the way for novel targeted therapeutic approaches for this debilitating condition.

Despite the progress made in the field of KOA research, several notable deficiencies persist in current investigations. First and foremost, the mechanical pressure experienced by the knee joint is not singular but rather a complex interplay of multiple factors. This complexity renders it extremely challenging to isolate and precisely control the mechanisms by which mechanical pressure alterations affect KOA. For instance, in real-life scenarios, the knee is simultaneously subjected to compressive, tensile, and shear forces during various activities, making it arduous to disentangle their individual contributions to the disease process.

Second, the different forms of cell death, such as apoptosis, autophagy, and ferroptosis, are intricately interconnected. Merely summarizing these individual cell death pathways is insufficient. A comprehensive understanding necessitates an in-depth exploration of their complex crosstalk and the underlying regulatory networks. This requires a multitude of additional studies, including those that use advanced molecular biology techniques to dissect the signaling cascades involved. In summary, the present study serves as a mere starting point. Moving forward, we are committed to delving deeper into the molecular mechanisms underlying KOA induced by abnormal mechanical pressure. This will involve a more systematic and comprehensive approach, integrating multidisciplinary research methods to gain a more profound understanding of this prevalent and debilitating condition.

Conclusions

Mechanical stress is a major factor contributing to KOA. Different mechanical stimulation stress modes influence chondrocyte matrix metalloproteinase production and cellular matrix metabolism. Mechanical stress-induced chondrocyte death and cartilage end-plate destruction, along with apoptosis, autophagy, ferroptosis, the inflammatory response, and ECM degradation, interact to form a collaborative signaling network. The activation of the PIEZO1 protein by mechanical stimulation plays a vital role in apoptosis, autophagy, and ferroptosis. Therefore, the diverse biochemical mechanisms triggered by PIEZO1 activation under mechanical stimulation may be the key to targeted KOA therapies.