Chondrocyte Senescence in Osteoarthritis: Potential Targets and Pharmacological Interventions

Abstract

Purpose

This review aims to elucidate the mechanisms underlying chondrocyte senescence in osteoarthritis (OA) from 4 core perspectives: extracellular inflammation, mechanical overload and stress, intracellular metabolic and signaling dysregulation, and genetics-related alterations. It further summarizes emerging therapeutic strategies targeting chondrocyte senescence to address the unmet clinical need for disease-modifying OA interventions.

Findings

Accumulating evidence indicates that chondrocyte senescence drives OA progression through multiple interconnected mechanisms. These include amplification of inflammation and extracellular matrix degradation via the senescence-associated secretory phenotype (SASP), disruption of anabolic-catabolic homeostasis, dysregulation of mechanotransduction pathways under excessive mechanical load, and reshaping of intracellular metabolism and redox balance. Additional contributing mechanisms involve epigenetic dysregulation, non-coding RNA–mediated gene modulation, and impaired autophagy. Therapeutic approaches under preclinical or clinical investigation encompass senolytic and senomorphic agents, chondroprotective biological materials, genetic or RNA-based interventions, as well as strategies targeting SASP modulation and extracellular microenvironment repair.

Conclusions

Chondrocyte senescence serves as a central convergent mechanism in OA pathogenesis and a promising target for disease-modifying therapies. Advances in mechanistic understanding and senescence-targeted interventions offer new avenues for translational innovation, though critical challenges related to specificity, safety, and long-term efficacy require further resolution.

Keywords

osteoarthritis cartilage chondrocyte cellular senescence

Introduction

Osteoarthritis (OA) is a global disease whose incidence is rising due to the aging population. In 2020, more than 500 million individuals worldwide were affected by OA.¹ By 2050, cases of knee OA are projected to increase by 74.9% compared to 2020.^2,3 OA also imposes significant economic and health burdens. In the United States, 540,000 individuals suffer from arthritis, the majority of whom have OA. Of these, 99% experience limitations in daily activities, leading to $6.5 billion in lost wages and over $10 billion in direct medical expenses.⁴ A cohort study in the United Kingdom found that all-cause mortality was nearly double in OA patients compared to non-OA individuals (13.52 vs. 7.14 per 1,000 person-years).⁵ Despite the disease’s impact, there are no disease-modifying drugs for OA due to its complex and unclear pathogenesis.

The risk factors for OA are multifaceted, including age, female gender, obesity, genetics, and severe joint damage, with aging being the most prominent.^6,7 OA progression involves structural changes in articular cartilage, subchondral bone, ligaments, joint capsule, synovium, subpatellar fat pad, and periarticular muscles. Cellular senescence and the senescence-associated secretory phenotype (SASP) are key contributors to these changes,⁸ with cartilage degeneration being a hallmark of the disease. Therefore, investigating the aging-related alterations within cartilage deciphers OA pathogenesis. Articular cartilage is a non-vascular tissue nourished by joint surface diffusion.⁹ It consists of chondrocytes surrounded by an extracellular matrix (ECM) made primarily of collagen (types II, IX, and XI) and proteoglycans, especially aggrecan.¹⁰ The renewal and homeostasis of the ECM rely on a delicate balance between chondrocyte-mediated synthesis and enzyme-driven degradation. The matrix-degrading enzymes include matrix metalloproteinases (MMPs), such as MMP3 and MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), with ADAMTS5 being particularly responsible for aggrecan degradation.^10,11 MMPs, especially MMP13, play a central role in the breakdown of cartilage collagen.¹² A shift toward a catabolic state in articular cartilage is observed in OA, driven by factors such as mechanical overloading, accumulated inflammatory mediators, metabolic disturbances, and cellular senescence.¹³ When cartilage catabolism outpaces anabolism, destruction ensues.

Chondrocyte senescence is a critical factor in both the initiation and progression of OA, making it a promising target for therapeutic intervention.^14,15 Currently, no effective treatments can reverse the pathological changes associated with OA. This review aims to comprehensively elucidate the underlying mechanisms of chondrocyte senescence and explore potential therapeutic interventions for OA.

OA Phenotype and Cellular Senescence

Cellular senescence is characterized by an irreversible arrest of the cell cycle, which reduces tissue regenerative capacity, promotes chronic inflammation, and even increases the risk of tumorigenesis in aging organisms.¹⁶ A hallmark of senescent cells is the secretion of the SASP, a pro-inflammatory milieu that induces secondary senescence in neighboring cells and disrupts tissue homeostasis, ultimately impairing repair and regeneration.¹⁷

Beyond these functional impacts, senescent cells also display both morphological and molecular changes as organisms age. Morphologically, they show increased cell volume and a flattened appearance. At the molecular level, senescent cells undergo genomic instability, telomere attrition, epigenetic modifications, impaired protein homeostasis, defective macroautophagy, dysregulated nutrient sensing, and mitochondrial dysfunction. These alterations converge to drive growth arrest, apoptosis resistance, and aberrant gene expression, accompanied by the secretion of SASP components, including interleukins (IL-1α, IL-1β, IL-6, IL-7, IL-8) and members of the MMP family (MCP1, MCP2, MMP1, MMP2, MMP3, MMP10, MMP13).^18,19

In both aging and OA progression, senescent cells and elevated SASP levels are detected in pathological cartilage and periarticular tissues but are rarely present in healthy joints or young individuals.^20
-22 This observation strongly suggests that the accumulation of senescent cells and SASP is a driving force behind OA onset and progression.²³ To identify senescent chondrocytes in this context, several characteristic features are commonly used such as telomere shortening, increased senescence-associated β-galactosidase (SA-β-gal) activity, and upregulated expression of p16.^9,24 The cyclin-dependent kinase inhibitor p16 plays a key role in enforcing cell-cycle arrest.²⁵ Although p16 does not directly affect SASP production, it is consistently overexpressed in senescent chondrocytes, making it a reliable marker of cellular senescence.²⁶

Based on the identification of senescent chondrocytes through these markers, experimental evidence further highlights their pathogenic role. For example, selective removal of SASP has been shown to delay the development of post-traumatic osteoarthritis (PTOA) in mice,²⁷ whereas intra-articular injection of senescent chondrocytes exacerbates OA pathology.²¹ These findings underscore that the accumulation of senescent chondrocytes disrupts cartilage homeostasis and sustains a pro-inflammatory microenvironment, creating a self-perpetuating cycle of degeneration.²⁴ Mechanistically, 2 primary pathways for chondrocyte senescence have been proposed: Intrinsic senescence, which arises from the telomere shortening; Extrinsic stress–induced premature senescence, triggered by oxidative stress or DNA damage (without impacting telomere length).^9,28,29 Given the inherently low proliferative potential of adult chondrocytes, the extrinsic stress–induced pathway is considered the more plausible mechanism in OA progression.^9,24 Therefore, understanding the mechanisms of chondrocyte senescence and SASP not only deepens our knowledge of OA pathogenesis but also provides a critical foundation for developing innovative, disease-modifying therapeutic strategies.

Causes and Mechanisms of Chondrocyte Senescence in OA

Extracellular Inflammation in Local Microenvironment

SASP has emerged as a crucial contributor to OA pathophysiology, with particularly significant roles in cartilage degeneration and synovial inflammation. SASP factors, produced by senescent cells, have been identified in OA tissues and synovial fluid. In these locations, they propagate secondary senescence, disrupt tissue homeostasis, and impair tissue repair and regeneration.³⁰

Diekman et al. highlighted that SASP generation and secretion are not strictly orchestrated to cell-cycle arrest. For instance, p16 knockout mouse chondrocytes, which are typically associated with senescence, do not exhibit a significant reduction in SASP factor release.²⁶ This finding underscores the complex and multifactorial mechanisms underlying SASP production in senescent chondrocytes. Through autocrine and paracrine signaling, SASP modifies the tissue microenvironment, hinders repair mediated by stem or progenitor cells, and induces senescence in neighboring cells, with chondrocytes being particularly susceptible. This creates a detrimental feedforward cycle that perpetuates tissue dysfunction and degeneration.^31,32 Pro-inflammatory cytokines, including IL-1β and TNF-α, exacerbate this cycle by disrupting mitochondrial function in human chondrocytes. This disruption includes mitochondrial DNA damage, reduced energy production, and impaired mitochondrial transcription, all of which further accelerate chondrocyte senescence.³³ Moreover, the accumulation of SASP factors triggers inflammatory pathways, shifting the balance from anabolic to catabolic processes in cartilage tissue. This imbalance not only accelerates cartilage breakdown but also contributes to subchondral bone remodeling, which are hallmarks of OA progression.¹² Collectively, these findings illustrate the central role of SASP in driving OA pathology and offer potential therapeutic targets to mitigate its impact.

Mechanical Overload and Stress

Obesity, deformities, and prolonged weight-bearing are established mechanical factors linked to cartilage degeneration and microstructural changes in subchondral bone. Such shared alterations have been observed in the majority of relevant studies. Research indicates that mechanical stress can affect chondrocyte development and maturation, thereby influencing ECM amount.³⁴ Moderate mechanical load can induce hypertrophy, whereas reduced mechanical load can cause atrophy. Overload causes damage to the collagen network and loss of proteoglycans. It also leads to a marked decrease in Collagen II secretion and a significant increase in SASP expression levels.³⁵ Transcriptionally, excessive mechanical stress can upregulate aging markers such as p16 and p21 in chondrocytes, which in turn lead to cellular senescence, impaired chondrocyte anabolism, and irreversible cartilage destruction.^35,36 These findings suggest that chondrocyte senescence occupies a relatively downstream position in OA induced by loading factors.

Beyond the direct effects of mechanical stress on chondrocytes and cartilage, the underlying molecular mechanisms involve specific mechanical loading-sensor molecules, as reported in several studies. A recent study confirmed that mechanical overload stimulates JNK signaling and promotes senescence of both cultured chondrocytes and mouse cartilage by reducing FBXW7 mRNA transcription and FBXW7-mediated MKK7 degradation.³⁷ MKK7 functions as an upstream kinase that activates JNK under toxic conditions, while its inhibitor, GADD45β-I, protects chondrocytes from IL-1β by inhibiting endoplasmic reticulum stress via sirtuin3 mediation.³⁸ In a rodent model of temporomandibular joint OA, mechanical stress-induced cellular senescence is mediated by YAP deficiency.³⁹ Moreover, mechanical overload has been observed to reduce Zmpste24 expression, leading to increased production of reactive oxygen species (ROS) and nuclear membrane instability, followed by chondrocyte senescence.⁴⁰ Zmpste24 is a zinc metalloproteinase that plays a crucial role in the maturation of Lamin A by cleaving prelamin A, a precursor protein.⁴¹ When Zmpste24 activity is impaired, the accumulation of immature prelamin A disrupts nuclear structure and mechanics, leading to genomic instability and DNA damage.⁴² Lamin proteins, key components of the nuclear envelope, include Lamin A, Lamin B, and their associated proteins. They are essential for nuclear integrity, and their dysfunction can result in DNA damage. Lamin B1 deficiency has been associated with altered chromatin structure and epigenetic changes linked to aging.⁴³ Piezo1, a mechanosensitive Ca²+ channel, is upregulated in senescent chondrocytes and aged mouse cartilage.⁴⁴ In advanced OA, elevated Piezo1 expression correlates with aging markers p16 and p21. Piezo1 contributes to chondrocyte senescence by sensing mechanical stress and promoting the release of SASP factors such as IL-6 and IL-1β,⁴⁵ thereby disrupting cartilage metabolism and accelerating OA progression. In addition, mechanical overload has been shown to downregulate miR-325-3p, leading to activation of the p53/p21 pathway and further promoting chondrocyte senescence.⁴⁶

It is noteworthy that adiposity itself could amplify the mechanical influences on chondrocyte aging by impacting cell metabolism,²² which is attributed to increased adipokines and inflammatory mediators released by the systemic adipose tissue pool.³⁰ Adiponectin and leptin are the most well-known adipokines in metabolism modulation. Similar to SASP, leptin also upregulates the expression of MMP1, MMP3, and MMP13 in chondrocytes and induces senescence by activating the p53/p21 pathway.⁴⁷ Therefore, obesity affects chondrocyte senescence and OA progression in both mechanical and endocrinal ways.

Targets of Intracellular Metabolism and Signaling Pathways

Mitochondrial dysfunction and oxidative stress matter in chondrocyte aging, dedifferentiation, and even apoptosis.¹⁴ Dysfunctional mitochondria enhance inflammation and catabolic mediators, thereby increasing cellular ROS.^19,36 These elevated ROS levels regulate chondrocyte senescence by activating the expression of multiple genes, including p53, JNK, and NF-κB.^48,49 Excess ROS triggers a DNA damage response that stabilizes p53, thereby activating the p53/p21/pRb/E2F axis to enforce cell-cycle arrest; in parallel, ROS activates stress kinases such as JNK, which (together with NF-κB) transcriptionally amplifies SASP components. Activation of the DNA damage repair response leads to cell-cycle arrest through the p53/p21/pRb/E2F and p16/pRb/E2F signaling pathways, ultimately leading to cellular senescence.³⁶ Under physiological conditions, low-level ROS is essential for maintaining cellular homeostasis and function.⁴⁸ However, an excessive accumulation of ROS due to aging-related factors or decreased antioxidant capacity contributes to cellular damage and senescence, promoting OA progression.^49,50 Mechanistically, ROS-driven activation of p53/p21 locks chondrocytes in an irreversible growth-arrested state, while ROS-JNK-NF-κB signaling promotes and sustains SASP. The SASP (e.g., IL-1β, IL-6, MMPs) in turn elevates intracellular ROS and reengages JNK/NF-κB signaling, forming a feedforward loop that accelerates cartilage matrix degradation and consolidates the OA phenotype.⁵¹ Moreover, aged individuals are more susceptible to oxidative stress than younger ones, creating a vicious cycle between oxidative stress and chondrocyte senescence and accelerating OA progression.⁵² Thus, ROS, JNK, p53/p21, and SASP are not isolated events but constitute an interconnected network in which ROS is both an initiator and a product. p53/p21 executes senescence, JNK/NF-κB shape the inflammatory SASP program, and SASP further fuels ROS production. They together drive OA pathogenesis.

Nevertheless, there is an intrinsic mechanism called mitophagy that eliminates excess ROS. Autophagy, defined as the selective removal of damaged organelles and proteins through lysosomal degradation, is essential for maintaining mitochondrial homeostasis and supporting cellular function, differentiation, and regeneration under conditions of nutrient deprivation, hypoxia, and ROS exposure.⁵³ Mitophagy, a subtype of autophagy, is thought to ameliorate the impacts of ROS by reducing excessive energy consumption, thereby avoiding chondrocyte senescence.³⁶ When autophagy or mitophagy is impaired, ROS accumulates, JNK and p53/p21 signaling are further reinforced, and SASP is upregulated. They then tighten the vicious cycle and accelerate chondrocyte senescence.⁵⁴ Its induction is regulated by a range of autophagy-related genes, including those encoding light chain 3 and p62. HyoJung’s team found that in mouse OA models induced by papain (a natural compound) and sodium iodoacetate (a synthetic compound), the expression levels of these 2 genes and PTEN-induced kinase 1 (Pink1) were increased.⁵⁵ Consistently, autophagy- and mitophagy-related genes are also highly expressed in human OA cartilage.⁵⁵ Similarly, animal studies by Wang et al.⁵⁶ confirmed decreased levels of light chain 3B and Bcl-2 in aging cartilage tissue. This demonstrates that autophagic activity decreases with age and increases in patients with OA.⁵⁷ Decreased autophagy in senescent chondrocytes in OA may disrupt this protective mechanism, thereby exacerbating OA progression. Thus, dysregulation of autophagy is closely related to OA pathogenesis. Targeting this ROS-JNK-p53/p21-SASP axis, either by restoring mitophagy or autophagy, dampening ROS, inhibiting JNK/NF-κB signaling, or modulating SASP, may therefore provide multi-node therapeutic leverage for disease modification in OA. HIF-1α-mediated mitophagy is protective in articular diseases by modulating chondrocyte apoptosis and senescence under hypoxic conditions.⁵⁸ Consequently, HIF-1α stabilization ameliorates cartilage degeneration in OA mouse models.⁵⁹ In a mouse PTOA model, endogenous glucocorticoid signaling upregulates catabolism through HIF-2α (another member of HIF family), leading to synovial activation, chondrocyte senescence, and cartilage degradation.⁶⁰ It is worth mentioning that carnitine palmitoyl transferase 1A, a rate-limiting enzyme for fatty acid oxidation, is highly expressed in senescent chondrocytes and mouse knee cartilage tissue.⁶¹ Its inhibition can alleviate senescence by relieving mitochondrial dysfunction and promoting mitophagy.⁶¹ Also, mechanical stress can induce mitochondrial dysfunction, leading to chondrocyte senescence.⁶² Conclusively, mitophagy is suggested to be a potential target for alleviating oxidative stress and intervening in OA.

Connexin 43 (Cx43) is an important regulator in musculoskeletal system.⁶³ In chondrocytes, it performs diverse functions, including mechanical transduction, differentiation, proliferation, and metabolic homeostasis.⁶⁴ The expression of Cx43 in OA cartilage is increased and significantly higher than control.⁶⁵ In human growth plates, Cx43 is predominantly expressed in the superficial zone, with a gradual decrease from the middle to the deep layers.⁶⁶ Overactive Cx43 sustains the immature chondrocyte phenotype by promoting the nuclear translocation of Twist-1 and enhancing expression of tissue remodeling factors and pro-inflammatory factors, including MMPs and IL-1β. These changes induce cellular senescence by upregulating p53, p16, and NF-κB, thereby contributing to the SASP production.⁶⁷ Small extracellular vesicles (EVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescence phenotype in targeted chondrocytes, synovium, and osteocytes, promoting inflammation and degenerative joint changes through SASP.⁶⁸

Regarding cell signaling pathways, the p38 MAPK, JNK, and NF-κB pathways are crucial in mediating the catabolic responses triggered by IL-1β and TNF-α.⁶⁹ Specifically, the p38 MAPK pathway, a component of the MAPK signaling family, contributes to cellular senescence, chondrocyte differentiation, MMPs synthesis, and pro-inflammatory factor production. The JNK pathway is recognized as a key mediator of cellular senescence and OA.⁷⁰ Cytokine-induced activation of JNK signaling exacerbates OA-related phenotypes by stimulating pro-inflammatory pathways and ECM degradation pathways in joint histiocytes.⁷¹ Human OA chondrocytes exhibit elevated levels of active JNK and p38 compared to healthy ones, verifying their correlations with OA progression.⁷² Li et al.⁷³ reviewed the role of the p38 MAPK signaling pathway in OA, emphasizing its contribution to chondrocyte senescence through the upregulation of MMPs, IL-1β, and TNF-α expression. Bone morphogenetic protein, a member of the TGF-β superfamily, plays an important role in bone and cartilage formation.⁷⁴ Blocking the activation of p38 and ERK signaling pathway by silencing bone morphogenetic protein 5 has also been demonstrated to inhibit chondrocyte senescence, apoptosis, and OA progression.⁷⁵ Similarly, antagonists of p38 and JNK can effectively reverse arsenic-induced chondrocyte senescence.⁷⁶ p38 inhibition has also been demonstrated to reverse hyperosmolar stress-induced chondrocyte senescence by downregulating HMG-box transcription factor 1, p16, Runx2, MMP13, Collagen X expressions, and upregulating Collagen II and SOX9 expressions. In addition, silencing HMG-box transcription factor 1 has also been shown to exert a protective effect against chondrocyte senescence.⁷⁷ These results suggest that targeting some components in the underlying signaling pathways of cartilage senescence provides new insights into OA therapy.

Surging OA occurrence in menopaused women implies the effects of estrogen on cartilage aging. Physiological levels of estrogen matter in rat mandibular condylar cartilage development by promoting the expression of Collagen II and Collagen X.⁷⁸ With aging, estrogen levels progressively decline. Before menopause, physiological concentration of 17β-estradiol can slow telomere shortening in mesenchymal stem cells (MSCs) and chondrocytes,⁷⁹ whereas postmenopausal decrease of its level show no significant effect. However, estrogen cannot prevent replicative senescence of somatic cells.⁷⁹ Studies have shown that, compared with untreated menopausal controls, the administration of 17β-estradiol and progesterone in ovariectomized mice can prevent cartilage degeneration.⁸⁰ In addition, the upstream hormone of estrogen, follicle-stimulating hormone, may induce chondrocyte dedifferentiation by suppressing Collagen II synthesis. The decline in Collagen II with aging can be reversed by blocking this upstream signaling.⁸¹ Meanwhile, estrogen receptor α plays a critical role in maintaining chondrocyte health by inhibiting DNA damage and cellular senescence. Loss of this receptor has been associated with increased senescence in human chondrocytes.⁸²

Therefore, estrogen signaling is nonnegligible in maintaining chondrocyte activity, stromal homeostasis, and delaying aging. During menopause, the correlation between their decline and chondrocyte senescence suggests that targeting estrogen signaling or its upstream pathways may be effective in intervening cartilage degeneration.

Genetics-Related Targets

Individual aging is associated with decreased chondrocyte mitotic activity and shortened telomere length, which may potentially contribute to chondrocyte senescence. However, inducing cellular mitosis in cartilage explants with cellular damage leads to increased SA-βgal activity and elevated expression of senescence markers. This implies that DNA damage precedes cell division in chondrocyte senescence. DNA damage initiates the DNA damage response,⁸³ a repair mechanism enabling cells to detect DNA damage, transmit related signals, and trigger a signaling cascade leading to cellular senescence and apoptosis.⁸⁴ The proteins involved in this process are particularly essential in the early stages, and their effectiveness depends on H2AX, a variant of histone H2A. Notably, γ-H2AX, phosphorylated at serine 139, serves as a well-established indicator of DNA double-strand breakages. A study showed that oxidative stress mimicked by H₂O₂ increased ROS levels, γ-H2AX, and p21 expression in rat chondrocytes.⁸⁵ This indicates that γ-H2AX could potentially serve as a marker for cellular senescence. As previously mentioned,³⁶ DNA damage can be attributed to the dysfunction of a complex network comprising Lamin A, Lamin B, and associated proteins, which induces senescence. Various genes were revealed to modulate this procedure. SIRT6, a member of the nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacetylase sirtuin (SIRT) family, protects skeletal system from bone and cartilage loss. Depletion of SIRT6 in human chondrocytes leads to senescence by inducing DNA damage and telomere dysfunction.⁸⁶ Telomere homeostasis depends on the normality of the Shelterin complex, which regulates telomere length, structure, and functional integrity. Telomere shortening can lead to instability of the Shelterin complex, thus disrupting the inhibitory link of the DNA damage response.³⁶ It is worth noting that oxidative stress can also induce telomeric instability, replicative senescence, and chondrocyte dysfunction in OA cartilage.⁸⁷ This suggests that oxidative stress, DNA damage, and chondrocyte senescence may be mutually reinforcing. The interferon gene stimulator STING can activate the cGAS-STING signaling pathway through cytoplasmic DNA accumulation, which occurs when chromatin leaks from the nucleus following DNA damage or telomere shortening. STING activation upregulates SASP and autophagy directly and promotes cell-cycle arrest indirectly.⁸⁸ It is also positively associated with mitochondrial dysfunction and epigenetic modifications, potentially accelerating cartilage aging.⁸⁸

In senescent cells, p53, p21, p16, and pRb expression is upregulated,⁸⁹ which has been linked to the initiation of chondrocyte senescence.^89,90 Among them, p53, p21, and pRb participate in the telomere shortening, and the cooperative action of p16 and pRb facilitates the aging process via mechanisms of stress-induced premature senescence.⁸⁹ These findings suggest that genetic intervention could be a potential approach for preventing chondrocyte senescence and treating OA. The underlying mechanisms discussed above that lead to chondrocyte senescence and the corresponding treatments (Fig. 1).

Figure 1.

Mechanism of chondrocyte senescence and its corresponding treatment. Left part: extracellularly, senescent cells promote the senescence of neighboring chondrocytes by promoting SASP expression, which continues exacerbating SASP secretion, forming a vicious circle. Intracellularly, senescent chondrocytes can cause mitochondrial dysfunction, promote oxidative stress, and produce excess reactive oxygen species to cause chondrocyte senescence. Within the nucleus, DNA damage and telomere abnormalities cause chondrocyte senescence. Right part: The drugs targeting chondrocyte senescence are depicted. TNFα = tumor necrosis factor α; IL-1 = interleukin 1; SASP = senescence-associated secretory phenotype; ROS = reactive oxygen species; LncRNA = long non-coding RNAs.

Intervention of Chondrocyte Senescence in OA

The Removal of Senescent Cells

Senolytics are a class of drugs that selectively target and eliminate senescent cells, which are a significant contributor to aging-related diseases due to their secretion of pro-inflammatory cytokines and tissue-destroying enzymes. These agents have demonstrated promising therapeutic effects in the treatment of age-related conditions such as Alzheimer’s disease, diabetes, and OA. This concept has been extensively verified in preclinical models, with some early-stage clinical trials confirming their potential, which suggests a promising future for senolytic drugs in clinical settings.⁹¹

Dasatinib and quercetin are 2 representative senolytics that can alleviate bone loss. It was also reported that weekly intake of them increased glycosaminoglycans, which can benefit the intervertebral discs.⁹² This finding raises an intriguing hypothesis: the similarities between intervertebral discs and articular cartilage could provide a therapeutic pathway, suggesting that these senolytics might similarly benefit articular cartilage in OA.⁹² Indeed, this cross-application between spinal health and joint health is an emerging area of interest, emphasizing the broader potential of senolytics beyond their immediate applications.

Furthermore, the Bcl-2 family inhibitor navitoclax, which targets key anti-apoptotic proteins such as Bcl-2, Bcl-xl, and Bcl-w, has been shown to induce apoptosis in senescent chondrocytes.⁹³ Navitoclax’s ability to alleviate OA symptoms is linked to its reduction of inflammatory cytokine expression in chondrocyte cultures and its promotion of cartilage matrix aggregation. In an experimental rat model of PTOA, intra-articular injection of navitoclax resulted in a reduction of pathological changes in both cartilage and subchondral bone, further supporting its potential as a therapeutic option for OA.⁹⁴ This highlights the growing recognition of senolytic drugs not only as anti-aging agents but also as direct modulators of disease progression, specifically in OA.²⁷ The results of these studies further suggest that targeting senescent cells within the joint could serve as a novel therapeutic method for managing OA. In addition, a peptide named FOXO4-D-Retro-Inverso has demonstrated senolytic effects to eliminate senescent chondrocytes and fibroblasts, thus treating OA.⁹⁵

In summary, senolytic therapies offer an innovative and potentially transformative approach to OA intervention by targeting the root causes of disease progression: the accumulation of senescent cells. The growing body of evidence points to a future where senolytics are integrated into clinical practice, offering new therapeutic options for aging-related joint diseases. The challenge remains to translate these exciting preclinical results into effective clinical treatments, but the outlook for senolytic-based therapies is undoubtedly promising.

Drugs Targeting SASP

Cellular senescence is often associated with the SASP, which involves the secretion of pro-inflammatory cytokines, chemokines, and ECM-degrading enzymes. Given the profound impact of SASP on the progression of age-related diseases, targeting the activated signaling pathways responsible for its synthesis and secretion represents a promising therapeutic strategy

Sirtuins-NAD⁺-dependent deacylases and ADP-ribosyltransferases, emerge as key regulators in modulating cellular processes such as DNA repair, apoptosis, inflammation, and metabolism.⁹⁶ To date, 7 members of the SIRT family have been identified (SIRT1 to SIRT7), each playing distinct roles in cellular homeostasis and aging. The sirtuin family, particularly SIRT1, has been proposed to ameliorate cellular aging in OA by suppressing SASP production.¹⁹ For example, omentin-1, an anti-inflammatory adipokine, has downregulated the expression of senescence factors (caveolin-1, p21, and PAI-1) induced by IL-1β, which was mediated by SIRT1.⁹⁷ Analogically, fisetin-loaded nanomaterials have been found to prevent IL-1β-induced inflammatory responses and chondrocyte senescence by activating SIRT1.^98,99 The activation of the Wnt/β-catenin signaling pathway has been linked to the promotion of chondrocyte senescence by reducing SIRT1 expression and elevating acetylated p53 levels. This effect can be mitigated by administering the pathway antagonist, dickkopf-1.¹⁰⁰ Also, fibroblast growth factor 21 has been demonstrated to alleviate senescence, ECM degradation, and chondrocyte apoptosis in OA through the activation of SIRT1/mTOR signaling pathway.¹⁰¹ Moreover, grapeseed proanthocyanidins have been identified to function similarly in OA via the DPP4/SIRT1 pathway.¹⁰² On the other hand, various compounds such as holomycin,¹⁰³ 1,25(OH) ₂D₃,¹⁰⁴ apremilast,¹⁰⁵ and hypoxia-pretreated MSCs¹⁰⁶ have been reported effective in reversing cellular senescence by modulating SIRT1. Beyond SIRT1, other sirtuin members such as SIRT3 and SIRT6 also contribute to protecting chondrocytes against senescence. Another member of the SIRT family, SIRT3, was found to delay chondrocyte senescence in OA by its overexpression and subsequent phosphorylation of the PI3K-AKT pathway, an effect induced by gastrodin.¹⁰⁷ Downregulation of SIRT4 has been shown to impair the cellular ability to eliminate damaged mitochondria by inhibiting the kinase PINK1 in chondrocytes. This inhibition results in ROS accumulation, which in turn accelerates chondrocyte senescence.¹⁰⁸ Studies have demonstrated that the injection of a SIRT4 lentivirus in mice OA model (medial meniscus destabilization) effectively inhibited the upregulation of key markers (such as MMP13, p62, p21, and p16) of senescence. In addition, the injection led to the restoration of the expression (such as Pink1, Col2a1, and light chain 3) of critical genes involved in mitochondrial function and cartilage integrity.¹⁰⁸ This indicates that intra-articular intervention to upregulate SIRT4 may be effective in mitigating oxidative stress and senescence, thereby protecting cartilage in OA treatment. Studies have shown that SIRT5 levels in cartilage decrease during aging, and the combination of SIRT5 deficiency with obesity exacerbates joint degeneration in mice in a sex-dependent manner,¹⁰⁹ suggesting that SIRT5 is an important regulator of chondrocyte metabolism. In another mouse OA model, SIRT6 overexpression displayed similar effects by inhibiting IL-15/JAK3/STAT5 signaling.¹¹⁰ Meanwhile, SIRT6 can also prevent premature aging of human chondrocytes by coordinating DNA repair and maintaining proper telomere function.⁸⁶ Upregulated SIRT6 expression by hydroxytyrosol has been proven to inhibit the levels of IL-1β and IL-6 in TNF-α-stimulated chondrocytes in a concentration-dependent manner, thus alleviating senescence by promoting autophagy.¹¹¹ Fisetin is a natural flavonol of the flavonoid family that is recommended as a senolytic drug. It can attenuate injury-induced chondrocyte SASP changes by targeting SIRT6.¹¹² Likewise, natural compounds such as ellagic acid,¹¹³ routine,¹¹⁴ and dendrobium officinale¹¹⁵ have exhibited the capacity to inhibit IL-1β-induced oxidative stress, enhance chondrocyte function, and suppress the expression of SASP factors and the senescence phenotype in chondrocytes, ultimately inhibiting apoptosis and senescence.

Notably, various compounds have been found to inhibit the STING-dependent NF-κB pathway, thereby reducing inflammation, ECM degeneration, and senescence in chondrocytes. Rhoifolin,¹¹⁶ proanthocyanidins B2 (a naturally occurring flavonoid compound),¹¹⁷ and itaconate¹¹⁸ can achieve those effects by binding to the NRF2 protein. Similarly, atractylolactone-III¹¹⁹ can also attenuate chondrocyte senescence by targeting the NF-κB pathway. Besides, resveratrol¹²⁰ can alleviate endoplasmic reticulum stress-induced joint degeneration by reducing the levels of TNF-α, IL-1β, MMP13, and p16. The bile acid receptor GPBAR1 and its agonist INT-777,¹²¹ as well as butyrophilin tartrate,¹²² have also been found to protect chondrocytes from senescence induced by IL-1β and TNF-α, respectively. Also, TNF-α-induced chondrocyte senescence can be mitigated by dipeptidyl peptidase-4 inhibitor, vildagliptin.¹²³ IL-1β upregulates the protein expression of MMP13 and the glycolytic enzyme M2 isoform of pyruvate kinase. Silencing its expression reduces p16 expression and modulates chondrocyte senescence.¹²⁴ PPARα ligands selectively eliminate senescent chondrocytes through apoptosis.¹²⁵ Fenofibrate, a PPARα agonist used to treat dyslipidemia in humans, diminishes senescence and inflammation in senescent humans and OA chondrocytes, while PPARα knockdown has the opposite effect.¹²⁵ Long-term clinical use of Huangqin Qingre Chubi Capsules has been shown to alleviate joint swelling and pain in OA patients. Mechanistically, these capsules derived from Chineses traditional medicine mitigate chondrocyte senescence in OA by modulating the STAG1/TP53/p21 signaling axis.¹²⁶

Another group of drugs named senomorphics can directly act on SASP to inhibit inflammatory signaling pathways and reduce tissue damage.¹²⁷ For instance, lebrikizumab/canakinumab, tocilizumab, etanercept, and CL82198 can target IL-1β, IL-6 receptor, TNF, and MMP-13, respectively.^19,128 The aforementioned senolytic regimen combining dasatinib and quercetin also reduces SASP release, promotes cartilage anabolism, and attenuates the activation of the NF-κB pathway.¹²⁹ Similarly, parthenolide can inhibit chondrocyte senescence by targeting the NF-κB/SASP signaling pathway.¹³⁰ In conclusion, the accumulating evidence suggests that targeting the molecular pathways involved in SASP, including sirtuins and other signaling cascades, holds great promise for the treatment of OA and other age-related diseases. By modulating these pathways, either through the activation of sirtuins or inhibition of inflammatory mediators, it may be possible to delay or even reverse the cellular aging processes that contribute to cartilage degeneration. As research progresses, the integration of senolytics, senomorphics, and other pathway-targeting therapies may revolutionize OA management, offering new hope to OA patients. Table 1 provides a comprehensive overview of the commonly used drugs for intervening in the inflammatory pathways associated with chondrocyte senescence.

Table 1.

Common Anti-Aging Drugs Acting on Inflammatory Pathways.

Drugs	Mechanisms	Effect	Ref.
omentin-1	Adjust SIRT1	Inhibits IL-1β-induced chondrocyte senescence	Chai et al.⁹⁷
Fisetin	Activate SIRT1	Inhibits IL-1β-induced chondrocyte senescence	Zheng et al.⁹⁸
dickkopf-1	Blocks SIRT1 downregulation	Inhibits IL-1β-induced chondrocyte senescence	Li et al.¹⁰⁰
Grape seed extract proanthocyanidins	Inhibition of DPP4, Activate SIRT1	Inhibits chondrocyte senescence	Wang et al.¹⁰²
Holomycin	IL-1β	Inhibits IL-1β-induced senescence	Pan et al.¹⁰³
1,25(OH)^-/-₂D₃	Upregulated SIRT1	Inhibits chondrocyte senescence	Chen et al.¹⁰⁴
apremilast	Adjust SIRT1	Inhibits IL-17-induced senescence	Wang et al.¹⁰⁵
Hypoxia pre-treated MSCs	-	Inhibits IL-1β-induced senescence	Yang et al.¹⁰⁶
Gastrodin	Upregulated SIRT3	Inhibits the aging of chondrocytes Improves mitochondrial function	Zhang et al.¹⁰⁷
Hydroxytyrosol	Upregulated SIRT6	Inhibits inflammatory response and chondrocyte senescence	Zhi et al.¹¹¹
Ellagic acid	Upregulated Nrf2 expression	Inhibits IL-1β-induced oxidative stress, apoptosis, and senescence	Zhu et al.¹¹³
Rupine	Inhibits the activation of PI3K/AKT/NF-κB and MAPK pathways	Inhibits IL-1β-induced chondrocyte apoptosis, senescence, and autophagic damage	Wan et al.¹¹⁴
Dendrobium	Reduces ROS Inhibits NF-κB activation	Inhibits IL-1β-induced SASP factor expression and senescence phenotype in chondrocytes and improves mitochondrial function	Chen et al.¹¹⁵
Rhoifolin	Binds to Nrf2 to inhibit the NF-κB pathway	Inhibition of IL-1β-induced expression of SASP factors and senescence phenotype in chondrocytes	Chen et al.¹¹⁶
Proanthocyanidins B2	Nrf2/NF-κB pathway	Inhibits IL-1β-induced SASP factor expression and senescence	Cai et al.¹¹⁷
Itaconate	Activate Nrf2, Inhibits STING-dependent NF-κB pathway	Inhibits inflammation, ECM degeneration, and senescence of IL-1β-stimulated chondrocytes	Ni et al.¹¹⁸
Atractylolactone-III	Reduced phosphorylation of IKKα/β, IκBα and p65 in the NF-κB pathway	Inhibition of the expression of chondrocyte senescence phenotype and ROS level	Xu et al.¹¹⁹
Resveratrol	Reduces senescent chondrocyte count and senescence marker expression	Inhibits chondrocyte senescence	Hecht et al.¹²⁰
INT-777	Improved IL-1β-induced chondrocytes entering the G0/G1 arrest phase and S and G2/M phases	Inhibits the expression of IL-1β-induced senescence-related proteins as well as the reduction of SIRT1	Huang et al.¹²¹
Butophenol tartrate	Inhibits NF-κB	Attenuated TNF-α-induced SASP factor production and chondrocyte senescence	Zhang et al.¹²²
Vildagliptin	Inhibits DPP4, Upregulated SIRT1	Improve TNF-α-induced chondrocyte senescence and inhibit chondrocyte senescence protein expression	Bi et al.¹²³
Fenofibrate	Increases autophagic flux	Inhibits chondrocyte aging and inflammation	Nogueira-Recalde et al.¹²⁵
lutikizumab	IL-Iβ	Inhibits chondrocyte senescence	Fleischmann et al.¹²⁸
canakinumab	IL-Iβ	Inhibits chondrocyte senescence	Fleischmann et al.¹²⁸
Tocilizumab	IL-6	Inhibits chondrocyte senescence	Coryell et al.¹⁹
Etanercept	TNF	Inhibits chondrocyte senescence	Coryell et al.¹⁹
CL82198	MMP	Inhibits chondrocyte senescence	Coryell et al.¹⁹

SIRT = sirtuins; IL = interleukin; DPP4 = dipeptidase-4; Nrf2 = nuclear factor erythroid 2-related factor 2; NF-κB = NF-kappa B; MAPK = mitogen-activated protein kinases; ECM = extracellular matrix; ROS = reactive oxygen species; SASP = senescence-associated secretory phenotype; TNF = tumor necrosis factor; MMP = matrix metalloproteinases.

Non-Coding RNAs

Epigenetic alterations play a critical role in the pathogenesis and progression of OA by modulating chondrocyte function and accelerating cellular senescence.¹³¹ Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as key regulators in cartilage breakdown and OA progression. These ncRNAs regulate gene expression at the post-transcriptional level and influence various cellular processes, including inflammation, apoptosis, and ECM degradation. Given their central role in OA, identifying and targeting these ncRNAs offers a promising avenue for developing novel therapeutic strategies aimed at modifying disease progression.

Zhu et al.¹³² discovered that miR-29b-5p is downregulated in OA cartilage, and its upregulation could inhibit MMPs and aging-related genes (p16/p21) through TET1, a translocation enzyme. Then they confirmed its therapeutic effects in improving cartilage degeneration by using an injectable bioactive self-assembled peptide nanofiber hydrogel to deliver agomiR-29b-5p.^132,133

MFG-E8 (lactomucin) is a secreted glycoprotein that is widely expressed throughout the body.¹³⁴ MFG-E8 can alleviate apoptosis, reverse cellular oxidative stress, and regulate the balance between osteoblasts and osteoclasts.^135,136 In another study, Lu et al.¹³⁷ identified it as a critical factor in restoring chondrocyte homeostasis and preventing senescence. Their study demonstrated that miR-99b-5p upregulation in human cartilage accelerated chondrocyte senescence and OA progression by inhibiting MFG-E8. This finding indicates miRNA-based treatments as a non-surgical intervention for managing OA. It is interesting that downregulated miR-325-3p in cellular oxidative stress induced by mechanical overload can activate the p53/p21 pathway and promote chondrocyte senescence,⁴⁶ highlighting a potential molecular target for integrative exercise therapy. Also, some miRNAs (miR-3-122p, miR-5-143p, miR-3-206p, miR-30, miR-5a-22p, miR-3-151p, and miR-5a-3358p) related to cellular oxidative stress provide targets for attenuating cellular senescence.¹³⁸ Another study has illuminated that senolytic treatment influences the expression of multiple miRNAs (miR-34a, -30c, -125a, -24, -92a, -150, and -186) linked to cartilage production,¹³⁹ regulating chondrocyte senescence.

Many other ncRNAs, including AC006064.4-201,¹⁴⁰ miR-140,¹⁴¹ lncRNA TCONS_00029778,¹⁴² miR-135b-5p,¹⁴³ SNORA80B-201,¹⁴³ RNU5E-1-201,¹⁴³ miR-330-5p,¹⁴⁴ miR-15a,¹⁴⁵ and circZSWIM6¹⁴⁶ have shown promise in alleviating chondrocyte senescence through a similar ncRNA-pathway regulatory mechanism. On the other hand, specific ncRNA like lncRNA ELDR,¹⁴⁷ has-piR-019102,¹⁴³ Linc00707,¹⁴⁴ and miR-33-5p¹⁴⁸ have been linked to speeding up chondrocyte aging. These particular ncRNAs offer innovative prospects for future precision therapies. These findings provide strong evidence that ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, can affect OA pathogenesis and progression by epigenetic modulations. As such, they offer innovative prospects for developing precision therapies in genetic approaches. Table 2 provides a summary of some ncRNAs involved in chondrocyte senescence.

Table 2.

ncRNAs Affecting Chondrocyte Senescence.

ncRNA	Mechanisms	Effect	Ref
miR-29b-5p	Inhibited the expression of MMPs and aging-related genes	Relieves chondrocyte aging	Zhu et al.¹³²
miR-99b-5p	Regulate MFG-E8	Accelerates the aging of chondrocytes	Lu et al.¹³⁷
miR-325-3p	Downregulated Trp53	Inhibits chondrocyte senescence	Zhao et al.⁴⁶
miR-3-122p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-5-143p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-3-206p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-30	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-5a-22p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-3-151p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-5a-3358p	Regulates cellular oxidative stress	Inhibits chondrocyte senescence	Chang et al.¹³⁸
miR-34a	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-30c	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-125a	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-24	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-92a	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-150	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
miR-186	Reacts to senolytic	To assess efficacy, Further research is needed	Jeon et al.¹³⁹
lncRNA AC006064.4-201	Down-regulation of aging marker expression	Inhibits chondrocyte senescence	Shen et al.¹⁴⁰
miR-140	Inhibits the expression of aging-related proteins	Inhibits chondrocyte senescence	Si et al.¹⁴¹
lncRNA TCONS_00029778		Promotes mechanical stress-induced cellular senescence	Zhang et al.¹⁴²
miR-135b-5p		Inhibits chondrocyte senescence	Chen et al.¹¹⁵
SNORA80B-201		Inhibits chondrocyte senescence	Zhang et al.¹⁴³
RNU5E-1-201		Inhibits chondrocyte senescence	Zhang et al.¹⁴³
miR-330-5p		Inhibits chondrocyte apoptosis and senescence	Qian et al.¹⁴⁴
miR-15a	Inhibits mRNA translation of β1, 4-GalT-I, phosphorylation of NF-κB	Inhibits chondrocyte ECM degradation and senescence	Wang et al.¹⁴⁵
CircZSWIM6	Regulates ECM metabolism and AMPK-related energy metabolism	Inhibits the expression of aging-related proteins	Gong et al.¹⁴⁶
lncRNA ELDR	Regulates histone modifications in IHH Promoter regions Activates hedgehog signaling	Promote chondrocyte aging	Ji et al.¹⁴⁷
has-piR-019102		Promote chondrocyte aging	Zhang et al.¹⁴³
LINC00707	Regulate FSHR, miR-330-5p	Promote chondrocyte apoptosis and aging	Qian et al.¹⁴⁴
miR-33-5p	Regulate SIRT6	Promotes IL-1β-induced senescence	Liu et al.¹⁴⁸
miR-26b-5p	Suppress asporin	Restores chondrocyte homeostasis and slows down chondrocyte aging	Liu et al.¹⁴⁹
miRNA-34a	Upregulated SIRT1	Inhibits the expression of aging-related proteins and alleviates chondrocyte senescence	Yan et al.¹⁵⁰

LncRNA = long non-coding; miRNAs = microRNAs; SIRT = sirtuins; MFG-E8 = milk fat globule-epidermal growth factor 8; ECM = extracellular matrix; AMPK = AMP-activated protein kinase; IHH = Indian hedgehog; FSHR = follicle-stimulating hormone receptor.

Small Molecular Drugs

Several small-molecule drugs have been identified as promising candidates for inhibiting chondrocyte senescence. These drugs act through various mechanisms, including regulating mitochondrial dysfunction, enhancing autophagy, inhibiting inflammatory signaling, and promoting cellular reprogramming. Their potential to modify OA progression provides exciting opportunities for therapeutic interventions aimed at slowing or even reversing cartilage degeneration. Etomoxir can reduce the level of carnitine palmitoyl transferase 1A, thus mitigating chondrocyte senescence by regulating mitochondrial dysfunction and enhancing mitophagy.⁶¹ Endothelin-1, initially identified as a potent vasoconstrictor, may trigger chondrocyte senescence through ROS induction. However, an in vitro study confirmed that ROS scavenger vitamin C can rescue this process by restoring mitochondrial dynamics.¹⁵¹ Knockdown of Tribbles homolog expression with small interfering RNAs has been demonstrated to delay chondrocyte senescence in vitro by enhancing autophagy.¹⁵² TFEB has been discovered to initiate the expression of multiple autophagy-related genes and lysosomal biogenesis, serving as a significant regulator of autophagic flux. TFEB overexpression can decrease SA-βgal activity and p16 expression in OA model mice, alleviating surgery-induced cartilage degradation, inhibiting chondrocyte apoptosis and senescence, and enhancing autophagic flux.¹⁵³ AURKB is identified as a crucial senescence-associated chromatin regulator, whose inhibitor barasertib could effectively reverse senescence and heterochromatin instability in chondrocytes, attenuating rat OA.¹⁵⁴ In another study, overexpression of CCN1 induces inflammatory secretion and can be rescued by siRNAs. Meanwhile, Tanshinone IIA has been employed to inhibit CCN1 production and decrease SASP, contributing to a preserved articular cartilage in OA models.¹⁵⁵ Similarly, olive-derived polyphenols like oleuropein decrease Cx43 levels and Twist-1 activity to alleviate cellular senescence in OA chondrocytes, synovial cells, and osteocytes. They can promote chondrocyte redifferentiation, restore ECM synthesis, and reduce inflammation and catabolism mediated by IL-1β, IL-6, cyclooxygenase-2, and MMP3.¹⁵⁶ β-hydroxybutyrate exhibits anti-aging effects in chondrocytes by binding to heterogeneous nuclear ribonucleoprotein A1 and inhibiting AKT phosphorylation and enhancing PTEN expression.¹⁵⁷ In a PTEN knockout mouse PTOA model, long-term administration of the antioxidant N-acetylcysteine inhibited chondrocyte senescence and slowed OA progression.¹⁵⁸ Recent studies have identified dozens of similar molecules. Astrasin has been observed to accelerate chondrocyte senescence and exacerbate chondrocyte degeneration by suppressing the TGF-β1-Smad2 pathway.¹⁴⁹ Since there is a notable downregulation of miR-26b-5p in OA cartilage, miR-26b-5p-asporin-Smad2 axis may offer a therapeutic avenue to delay chondrocyte senescence.¹⁴⁹ In another study, metformin was found to slow down chondrocyte senescence by inhibiting the expression of miR-34a and enhancing SIRT1 expression in OA cartilage.¹⁵⁰ WNT1-inducible signaling pathway protein 1 can delay chondrocyte senescence and apoptosis by regulating the αvβ3 receptor and the PI3K/AKT pathway in OA.¹⁵⁹ Delivery of FGF18 mRNA via lipid nanoparticles can activate the FOXO3a-mediated autophagy pathway, thereby preventing chondrocyte degeneration and senescence.¹⁶⁰ Uridine, a bioactive compound isolated from plants or animals, has shown the ability to decrease p16 and p21 expression and SA-β-gal level.¹⁶¹ Psalmotoxin-1, an inhibitor of acid-sensitive ion channel 1a, can protect cartilage, restore Laminin B1 levels, and inhibit chondrocyte senescence in a rat OA model.¹⁶² These findings underscore the growing list of small molecular drugs and compounds that hold therapeutic potential for modifying OA progression. From mitochondrial regulation and autophagy enhancement to the modulation of inflammatory pathways and senescence-related gene expression, these molecules provide diverse strategies for targeting the underlying mechanisms of OA. As research in this area continues to evolve, they may lead to the development of more effective and precise therapies for OA, ultimately improving patient outcomes and quality of life.

Biological Therapies

EVs are tiny membrane-bound vesicles released by cells to mediate cellular communication. EVs, including exosomes, are released by virtually all cell types.¹⁶³ Nowadays, they are found eligible in curing diseases associated with cellular senescence.¹⁶⁴ The EVs from the plasma of young mice reverses degenerative changes and age-related dysfunction by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.¹⁶⁵ They can also be modified or incorporated into biomaterials to enhance targeting precision and improve therapeutic efficacy. For example, exosomes carrying lncRNA MEG-3, derived from human bone marrow MSCs have reduced IL-1β-induced senescence and apoptosis in chondrocytes.¹⁶⁶ Intra-articular injection of lncRNA H19-enriched exosomes derived from umbilical cord MSCs promotes long-lasting cartilage repair.¹⁶⁷ EVs derived from induced pluripotent stem cells significantly enhance the proliferation of primary human chondrocytes and inhibit IL-1β-induced chondrocyte senescence by regulating p21 and Collagen II expression.¹⁶⁸ Furthermore, exosomes released by adipose-derived stem cells under hypoxic conditions demonstrate a chondroprotective effect, preventing cartilage erosion induced by ADAMT13, MMP1, and IL-1β.¹³⁸ These studies showed the potential of exosomes and their derivatives as targeted biotherapies in addressing chondrocyte aging.

However, several challenges remain before exosome-based therapies can be successfully translated into clinical applications. Exosomes are present in all biological fluids and are secreted by all cell types.¹⁶³ Their isolation and characterization methods are not yet standardized, and each approach has inherent advantages and limitations.^169,170 For example, ultracentrifugation, although considered the gold standard for exosome isolation, may cause mechanical damage and has low portability.¹⁶⁹ These factors contribute to the heterogeneity and variability of EV composition, which may be influenced by cell source, culture conditions, and isolation techniques. The lack of standardized protocols for EV production, purification, and characterization limits reproducibility across studies.¹⁷¹ Furthermore, scaling up EV production for clinical use poses technical and economic challenges, especially when large-scale manufacturing is required.¹⁷² Choosing cell source also raises safety and efficacy concerns. Some stem cell–derived EVs may carry unwanted components or induce off-target effects.¹⁷³ Potential immunogenicity is another concern, particularly when EVs are derived from allogeneic or xenogeneic sources, as these may provoke adverse immune responses in recipients.

These limitations underscore the need for rigorous quality control and regulatory standards in EV-based therapeutic development. Exploring strategies to modify EV surface properties for targeted delivery, as well as engineering biomaterial systems and nanoplatforms to protect EVs during circulation and enable their controlled release at specific sites, may further enhance their therapeutic efficacy.¹⁷⁴

The embryological relationship between cartilage and synovium merits attention. The presence of MSCs from the synovium, an important component of the MSC family, possesses strong chondrogenic and tissue repair potential.¹⁷⁵ Also, intra-articular injection or implantation of MSCs has shown promising therapeutic outcomes in both animal models and human studies.¹⁷⁶ Nevertheless, these approaches remain insufficient for the complete repair of articular cartilage defects, and the relationship between cartilage regeneration and symptom relief in OA remains unclear.

Diverse drug delivery approaches, especially biomaterials, have been developed to penetrate the avascular joints; however, the dense cartilage matrix presents obstacles. Overcoming these barriers enhances drug bioavailability in modulating chondrocyte senescence. Zhang et al.¹⁷⁷ introduced an innovative hyaluronic acid granular hydrogel with enhanced degradation resistance, which attenuated chondrocyte senescence by inhibiting the NF-κB signaling pathway in a mouse PTOA model. Maumita et al.¹⁷⁸ developed a hydrogel derived from amniotic tissue as a carrier for adipose-derived stem cells, which suppressed the catabolic response of IL-1β and inhibited the Wnt/β-catenin signaling pathway. Electrostatic interactions enable rapamycin-loaded cationic liposomes to selectively target negatively charged cartilage, maintaining cartilage homeostasis by enhancing autophagy, effectively reducing friction, and alleviating friction-related disorders such as OA.¹⁷⁹ In addition, loading rapamycin into poly (lactide-co-glycolide) microparticles induces autophagy and inhibits senescence in primary human articular chondrocytes from OA patients.¹⁸⁰ Biomaterial modifications, precise delivery, and controlled release are crucial for intervening in chondrocyte senescence and OA progression.

Most biomaterials are engineered at the nanoscale, enabling them to readily traverse multiple biological barriers and undergo nonspecific endocytosis by immune cells.¹⁸¹ However, concerns remain regarding potential risks such as transient organ accumulation, abrupt release, or unintended off-target retention. Local drug delivery offers a promising strategy to overcome the limitations of conventional dosage forms by enhancing drug bioavailability and significantly reducing systemic side effects. Various physical and chemical permeation enhancement techniques such as iontophoresis, ultrasound, heat, microneedles, and chemical enhancers have been investigated for transdermal delivery of OA therapeutics.¹⁷⁰ For example, transdermal delivery overcomes the skins stratum corneum barrier and the dense collagenous matrix within the joint cavity to achieve effective drug penetration and retention. Despite these encouraging advancements, biomaterial-based therapies still face translational barriers. Polymers are not inherently toxic, residual polymer monomers may promote apoptosis or genotoxicity.¹⁸² Thus, biocompatibility, degradation kinetics, and potential inflammatory responses remain key concerns.¹⁸³ To address these issues, achieving controlled and sustained drug release at the target site without premature leakage is technically required. Manufacturing complexity, batch-to-batch consistency, and regulatory approval processes should also be considered toward the clinical deployment of these advanced delivery systems.

In summary, exosomes and advanced biomaterials represent cutting-edge approaches in OA treatment, both in drug delivery and disease modification.

Prospects

As our understanding of OA pathogenesis deepens, numerous preclinical medications have shown promising potential, alongside drug delivery systems tailored to articular cartilage’s microenvironment and metabolism. However, key challenges persist in OA pharmacotherapy: its multifactorial progression limits single-factor targeting efficacy; patient heterogeneity complicates clinical trial design; and articular cartilage’s dense structure, coupled with its isolation from subchondral bone, hampers systemic drug delivery. Notably, cellular senescence unifies multiple OA pathogenic pathways including inflammation, mechanical overload, and metabolic dysregulation. Targeting senescent chondrocytes and modulating SASP could yield broader, more sustained effects than single-pathway interventions, making anti-senescence therapies both a key research direction and a potential breakthrough to overcome current limitations. In addition, regenerative medicine approaches like personalized in vitro cartilage organoids may offer promising alternatives. OA pharmacotherapies are expected to be more comprehensive and precise, thereby improving patient prognosis.

Footnotes

Acknowledgements

Figure 1 was created with .

ORCID iDs

Dunyong Tan

Jiawei Guo

Wencui Li

Author Contributions

Dunyong Tan wrote the manuscript. Jiawei Guo, Tianyu Wang, and Siyao Yang corrected and filed up the references. Jiawei Guo and Wencui Li designed and corrected the whole manuscript. Jianquan Liu proposed the information. Daping Wang and Wencui Li supervised the process. Daping Wang and Wencui Li funded the project. All authors contributed to the article and approved the submission.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Shenzhen Science and Technology Program (JCYJ20230807115121043), the China Postdoctoral Science Foundation (2023M742413), the China University Industry-University-Research Innovation Fund (2021JH037), the Natural Science Foundation of Guangdong Province (2021A1515010706), the international cooperation project of Shenzhen Science and Technology Innovation Commission (GJHZ20210705142007023) and the Natural Science Foundation of Guangdong Province (2023A1515010102).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Not applicable.

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