Effects of the space environment on articular cartilage homeostasis: a review

Abstract

Long-duration spaceflight poses risks to musculoskeletal health, yet articular cartilage remains understudied. This review explores how microgravity and radiation compromise its homeostasis. Mechanical unloading suppresses chondrocyte metabolism and disrupts extracellular matrix equilibrium. Concurrently, radiation, oxidative stress, and immune activation induce DNA damage, mitochondrial dysfunction, and senescence, exacerbating matrix degradation. We assess physical, nutritional, and pharmacological countermeasures, highlighting the need for integrated strategies protecting joints during space exploration.

Introduction

With the continuous advancement of space technology, space exploration, crewed deep-space missions, and commercial spaceflight have become increasingly frequent. Astronauts are now spending longer periods in space, shifting from short-term stays to medium- and long-duration missions. Prolonged exposure to the space environment, which is characterized by microgravity, radiation, and hypoxia, leads to a series of physiological changes that can cause various health problems, including reduced immunity, cardiovascular dysfunction, ocular disorders, nasal congestion, and sleep disturbances¹. In addition, the space environment also affects the musculoskeletal system. A large number of studies have shown that the space environment can cause bone loss and muscle atrophy, and extensive research has been conducted to explore the underlying mechanisms and develop effective countermeasures. Compared with bone and skeletal muscle, articular cartilage, which is a key structure for maintaining normal joint function, has received relatively little attention regarding its adaptive changes in the space environment².

Articular cartilage is an avascular and aneural tissue whose metabolic activity relies heavily on mechanical loading. In the microgravity environment, the absence of normal mechanical stress leads to mechanical unloading of the cartilage, which may disrupt its normal metabolic processes. In adult humans, articular cartilage has a very limited capacity for self-renewal, and chondrocytes account for only about 1% to 10% of the total weight of the cartilage tissue³. Therefore, once cartilage is damaged, the repair process is usually slow and incomplete, and the adverse effects on the tissue may persist for months or even years⁴. The cartilage health of astronauts may be chronically threatened, potentially leading to the development of osteoarthritis (OA). Such degenerative changes can significantly impair daily functional capacity, reduce quality of life, and increase the economic burden associated with medical treatment and rehabilitation⁵. In addition, specific factors in the spaceflight environment, such as radiation, hypoxia, and circadian rhythm disruption, may also exert potential effects on the articular cartilage of astronauts. Therefore, a better understanding of how the space environment influences cartilage physiology, as well as the development of effective preventive and rehabilitative strategies, is of great importance.

This review aims to explore the underlying mechanisms of cartilage adaptation to space conditions and to summarize current countermeasures for protecting joint health during spaceflight. It provides a novel and comprehensive analysis by integrating multiple environmental stressors and underlying molecular mechanisms. By bridging these complex biological processes with a structured overview of imaging, histological, and molecular evaluation methods, this work presents a holistic framework necessary for ensuring musculoskeletal health during future long-duration deep-space exploration missions. Table 1.

Table 1.

Consolidation of 2021–2025 spaceflight and advanced bioengineering cartilage research

Study	Model Type	Key Endpoints Monitored	Main findings
Patron et al.28	Human Astronauts	Plasma inflammatory and tissue deterioration markers	Evaluated the early onset of tissue deterioration; confirmed significant alterations in systemic inflammation and musculoskeletal degradation markers within the initial 17 days of microgravity exposure.
Liphardt et al.40	Human Astronauts	Urinary uCTX-II (a marker for type II collagen degradation) normalized to creatinine levels	Microgravity significantly increased cartilage degradation; levels peaked at 4 months in-flight and remained elevated for at least 1 month after returning to Earth
Kwok et al. 100	C57BL/6 mice	Medial knee cartilage and meniscal degradation (via microCT, histology, and biochemical/proteomic markers) in mice	Reduced weight-bearing induced arthritic changes in both cartilage and meniscus; exercise during readaptation successfully promoted the recovery of cartilage volume and thickness
Klarmann et al.8	3D Bioprinted Human Meniscus	Tissue macroscopic shape fidelity, construct homogeneity	Successfully bioprinted full-scale, avascular human meniscus tissue on-orbit, leveraging microgravity to prevent structural collapse without the need for toxic chemical scaffolding.
Chen et al. 85	DNA-inspired Janus Base Nanomatrix (JBNm)	Nanoparticle self-assembly, structural homogeneity	In-space fabrication yielded larger JBNm bundles with superior homogeneity compared to Earth controls; successfully penetrated dense cartilage to deliver therapeutics, preventing microgravity-induced degradation.
Aissiou et al.66	Bioengineered Human Cartilage	Sex-specific transcriptomics (SABV)	Female-derived chondrocytes exhibited unique upregulation of WNT7B and WNT9A, accelerating matrix catabolism compared to male donors under unloading conditions.

Microgravity simulation

In vitro and bioengineered models

Researchers have developed various ground-based facilities (GBFs) that can simulate microgravity conditions for cell culture, supporting studies in life sciences and tissue engineering. These simulation approaches enable the alteration of gravitational conditions on Earth, allowing investigation of how gravity affects diverse intracellular and intercellular processes, and providing essential preparation for future space missions⁶. While traditional rotating wall vessel (RWV), random positioning machine (RPM), and fast-rotating clinostat (FRC) systems have been widely used, advanced Microphysiological Systems (MPS) such as the human Cartilage-Bone-Synovium (CBS) “Joint-on-a-Chip” are now prioritized because they better recapitulate multi-tissue interactions, dynamic fluid flow, and physiologically relevant joint microenvironments⁷.

Recent breakthroughs in space-based bioengineering have demonstrated the feasibility of fabricating macro-scale musculoskeletal tissues in microgravity, notably through the BioFabrication Facility (BFF) aboard the International Space Station (ISS). In recent missions, human meniscus tissues bioprinted on-orbit successfully maintained overall shape fidelity. However, biomechanical evaluations revealed a critical challenge: the space-printed constructs exhibited a Young’s modulus approximately four times lower than their Earth-based controls (E_space = 0.25 E_earth)⁸. To resolve this mechanical discrepancy and ensure structural viability for load-bearing implantation, future in-space manufacturing protocols must integrate post-print mechanical conditioning bioreactors and optimize bioink crosslinking strategies to enhance tissue maturation in the absence of gravity.

Simulation of microgravity in rodents

In rodents, the primary method for simulating microgravity is hindlimb unloading (HLU), also known as hindlimb suspension or antiorthostatic suspension⁹. In this model, the tail of the rodent is suspended using a pulley system installed above the cage, which lifts the hind limbs and keeps them in an unloaded position. After an adaptation period, the animals are able to move freely within the cage using only their forelimbs, while maintaining otherwise normal behavior. This method not only simulates the mechanical unloading experienced by joint cartilage but also reproduces other physiological alterations observed in microgravity, such as cephalad fluid shift and changes in cardiovascular loading. Therefore, it has been widely used in studies of space biology and aerospace medicine.

Simulation of microgravity in humans

The 6° head-down bed rest (HDBR) model is a ground-based analog used to simulate the effects of microgravity on humans and is generally regarded as the gold standard for human microgravity simulation¹⁰. In this model, participants lie in a bed tilted downward at a 6° angle, with the head positioned below the horizontal plane. They are not allowed to raise their heads or get up, and all daily activities are performed while remaining in bed. This model reproduces many of the physiological effects of microgravity. It not only simulates gravitational unloading but also mimics the cephalad shift of body fluids¹¹.

Simulation of space radiation

Ground-based accelerators can generate high-energy protons with specific types and energy levels to simulate cosmic rays and high-energy particles encountered in space. They are widely used to study the effects of radiation on cellular DNA, tissue damage, and carcinogenic risk¹².

Simulation of other environmental factors

To more realistically reproduce the complex conditions of space, researchers have used specialized chambers or bioreactors to simulate environmental factors such as hypoxia, elevated CO₂, and closed-loop systems. These approaches allow for a more accurate replication of the multiple stressors encountered during crewed space missions¹³.

Articular cartilage degeneration and its evaluation methods

The degeneration process of articular cartilage

Early degeneration of articular cartilage is often characterized by alterations in the composition of the extracellular matrix (ECM), including the loss and structural disruption of proteoglycans (PGs) and collagen fibers. The reduction of PGs content and disintegration of the collagen network within the ECM decrease the permeability and water-retention capacity of cartilage, leading to a loss of bound water, an increase in free water, and the development of microscopic edema and abnormal hydration within the tissue¹⁴. As degeneration progresses into the middle and late stages, the cartilage exhibits pronounced edema, fissuring, surface fibrillation, and even tissue rupture, with structural damage becoming increasingly severe.

Early degeneration of cartilage is often asymptomatic; however, timely assessment and intervention at this stage can help slow disease progression and prevent the onset of osteoarthritis. Therefore, detection and evaluation during the early stage of degeneration are of great importance. At present, various approaches—including imaging, histological, and molecular biomarker analyses—have been applied to monitor cartilage degeneration at different stages, and the choice of evaluation method should be tailored to the sensitivity required for each phase.

Imaging evaluation

X-ray radiography has limited capability in visualizing non-mineralized cartilage tissue. It primarily evaluates changes in joint space width, which indirectly indicate cartilage loss, and is commonly used for grading osteoarthritis. Therefore, it is more suitable for assessing cartilage degeneration in the late stages of the disease. Ultrasound (US) is an economical and convenient imaging tool that enables real-time dynamic observation. However, its imaging depth and spatial resolution are limited, making it difficult to assess deep articular cartilage. Computed tomography (CT) can detect subtle changes in subchondral bone, evaluate bone mineral density, and assess cartilage calcification. Nevertheless, its ability to differentiate non-mineralized cartilage tissue remains limited, and it is therefore mainly used to evaluate osseous changes in advanced degeneration, with relatively low sensitivity for detecting early cartilage deterioration¹⁵.

Magnetic resonance imaging (MRI) not only allows morphological assessment of cartilage thickness and volume through conventional sequences but also enables quantitative analysis of compositional changes within the cartilage. For example, T1ρ mapping can quantitatively evaluate the proteoglycan content in cartilage, as the T1ρ relaxation time is negatively correlated with the concentration of proteoglycans¹⁶. T2 mapping is sensitive to the water content and the anisotropic organization of collagen fibers within articular cartilage, while the correlation between T2 relaxation time and proteoglycan concentration is relatively weak¹⁶. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) reflects the glycosaminoglycan (GAG) content within cartilage and thus provides an indirect assessment of proteoglycan changes¹⁷. Ultrashort echo time magnetic resonance imaging (UTE-MRI) is useful for visualizing the deep and calcified zones of articular cartilage. These techniques enable the detection of changes in cartilage matrix composition before the onset of clinical symptoms, thereby providing important support for the early evaluation of cartilage degeneration.

Histological and pathological evaluation

In clinical studies, arthroscopy allows direct visualization of the surface morphology of articular cartilage. However, it is an invasive procedure and therefore not suitable for early-stage population screening. In basic research, hematoxylin and eosin (HE) staining can be used to visualize the distribution, arrangement, and morphological changes of chondrocytes. During cartilage degeneration, a decrease in cell number, disorganized arrangement, and vacuolar degeneration or apoptosis can be observed, often accompanied by irregularities on the cartilage surface. Safranin O staining is commonly applied to assess proteoglycan content. In normal cartilage, the extracellular matrix stains bright red, and a reduction in staining intensity indicates matrix degradation. Toluidine blue staining is mainly used to evaluate glycosaminoglycan content. Combined with the Mankin and OARSI histological scoring systems, these staining methods enable semiquantitative grading of cartilage degeneration¹⁸.

Molecular evaluation

Articular cartilage is composed of chondrocytes and ECM. Specific molecules produced during cartilage metabolism can rapidly respond to alterations in biological and mechanical environments. These molecules serve as biomarkers that reflect early changes in cartilage metabolism and structure¹⁹.

The main components of the cartilage matrix include type II collagen, proteoglycans, glycoproteins, and water. Type II collagen forms a fibrous network that provides tensile strength to the cartilage. In animal studies conducted under microgravity exposure, disruption of the type II collagen network has been observed to occur at an early stage¹⁹. Therefore, degradation products of type II collagen, such as C-terminal cross-linked telopeptide of type II collagen (CTX-II), serve as important biomarkers for evaluating the extent of articular cartilage degeneration. Proteoglycans provide compressive resistance to cartilage, and studies have suggested that aggrecan fragments and their specific epitopes, such as aggrecan ARGS neoepitope (ARGS) and chondroitin sulfate 846 epitope (CS846), released during proteoglycan degradation, may serve as potential biomarkers of cartilage turnover²⁰. In addition, glycoproteins play an important role in cell–matrix interactions and matrix stabilization. Among them, cartilage oligomeric matrix protein (COMP) is a non-collagenous glycoprotein within the extracellular matrix, and its level is closely associated with cartilage degradation. Studies have suggested that the turnover of COMP fragments may be a key factor regulating the balance between cartilage formation and breakdown²¹. Related studies have found that individuals with knee osteoarthritis, rheumatoid arthritis, or exercise-induced discomfort exhibit higher levels of COMP²². In contrast, prolonged bed rest in healthy individuals has been shown to reduce serum COMP concentrations²³.

During cartilage degeneration, chondrocytes secrete various metalloproteinases. Among them, matrix metalloproteinases (MMPs) primarily target collagen fibers, regulating the balance of structural proteins within articular cartilage and playing a critical role in the response to local mechanical loading changes²⁴. Studies have shown that the serum levels of MMP-1, MMP-3, MMP-9, and MMP-13 respond to mechanical loading. Among these enzymes, MMP-13 expression is markedly upregulated and is considered a key factor contributing to excessive degradation of type II collagen and disruption of matrix stability. In addition, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, particularly ADAMTS-5, participates in the metabolic turnover of proteoglycans. Enhanced ADAMTS-5 activity leads to excessive proteoglycan degradation and further compromises cartilage integrity. Leong et al.²⁵ subjected rats to hindlimb unloading and examined the serum levels of cartilage-related biomarkers. They found that the mRNA expression of MMP-3 increased as early as 6 h after immobilization. Enzymatic activity began to rise after 1 day of unloading and persisted for 21 days, indicating that mechanical unloading may induce an early response in both enzyme activity and gene expression.

Inflammatory cytokines also play an important role in cartilage degeneration. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) can accelerate matrix degradation by activating downstream signaling pathways²⁶. Studies have demonstrated that the nuclear factor kappa B (NF-κB)– SRY-box transcription factor 9 (SOX9) signaling pathway plays a critical role in cartilage degeneration during osteoarthritis. Proinflammatory cytokines such as IL-1β and TNF-α can suppress SOX9 expression by activating the NF-κB pathway, thereby leading to impaired chondrocyte differentiation and reduced matrix synthesis²⁷.

Understanding the temporal kinetics of these molecular alterations is critical for developing in-flight monitoring strategies. Recent data from the AX-1 mission highlight a rapid catabolic shift in the joint microenvironment, demonstrating significant increases in the plasma levels of matrix metalloproteinases (MMP-1 and MMP-13) within the first 17 days of exposure to microgravity²⁸. Utilizing these precise temporal kinetics, we suggest that an operational framework can be established to distinguish between early reversible injury and subsequent irreversible damage in spaceflight²⁹. During the initial phase of unloading, cartilage typically undergoes a reversible injury driven primarily by aggrecan depletion; at this stage, the structural integrity of the extracellular matrix remains potentially salvageable upon mechanical reloading³⁰. However, if the catabolic stimulus persists without intervention, the sustained elevation of MMP-13 inevitably leads to irreversible damage, which is physically characterized by the permanent cleavage and disruption of the type II collagen network³¹. This critical transition from reversible aggrecan loss to irreversible collagen breakdown can be clinically supported and dynamically tracked in astronauts by monitoring specific biomarkers, most notably the elevation of urinary C-telopeptide of type II collagen (uCTX-II)³².

At present, although cartilage-related biomarkers have shown significant value in basic and translational research, they have not yet been widely applied in clinical diagnosis, and their specific clinical utility requires further exploration and validation.

Effects of the space environment on articular cartilage

Microgravity

Microgravity is the most characteristic feature of the space environment and a key factor influencing the adaptive changes of articular cartilage in astronauts. Under Earth’s gravity, weight-bearing activities such as standing and walking are essential for maintaining the structure and function of articular cartilage. However, in a weightless environment, mechanical loading is markedly reduced, resulting in decreased joint contact pressure, slower interstitial fluid flow within the cartilage, and disrupted balance between matrix synthesis and degradation. In addition, microgravity-induced fluid redistribution further affects nutrient transport and the removal of metabolic waste in cartilage, a tissue that lacks its own blood supply.

Articular cartilage is avascular and relies primarily on synovial fluid for nutrient delivery and metabolic waste removal through diffusion and convective transport³³. The circulation of synovial fluid within the joint cavity and its exchange with the cartilage matrix are driven by cyclic joint motion, which generates a pumping effect via alternating compression and decompression³⁴. In the microgravity environment, reduced mechanical loading and diminished dynamic joint motion impair this pumping mechanism, resulting in potential stagnation of synovial fluid circulation and compromised nutrient transport to chondrocytes². Additionally, the cephalad fluid redistribution characteristic of microgravity and simulated by head-down bed rest may alter hydrostatic pressure gradients across the synovial membrane, thereby influencing synovial fluid production, volume, and composition³⁵. Terrestrial joint immobilization studies, which closely mimic the unloading and reduced motion experienced in space, have demonstrated decreased hyaluronan concentration in synovial fluid as well as reduced levels of cartilage and synovium metabolic markers³⁶. A pilot ultrasound study in astronauts after an 18-day International Space Station (ISS) mission observed no statistically significant changes in knee synovial fluid depth post-flight, suggesting that short-duration exposure combined with exercise countermeasures may limit acute alterations, although longer missions warrant further investigation³⁷.

In a 21-day 6° head-down tilt bed rest experiment involving 12 healthy male volunteers, changes were observed in cartilage homeostasis biomarkers, which did not return to baseline within six days of reambulation. The degradation of type II collagen indicated that cartilage metabolism had shifted toward a catabolic state under unloading conditions³². Ground-based animal studies have shown that only 6–8 weeks of unloading can lead to a significant reduction in cartilage proteoglycan content, as indicated by a 5–10% increase in T1ρ values, along with decreased metabolic activity. Moreover, in some regions, these changes were not fully restored even after four weeks of reloading³⁸. Steinwerth et al.³⁹ cultured human primary chondrocytes and the C28/I2 cell line under simulated microgravity conditions and observed upregulation of MMP-1, MMP-3, and MMP-13, along with altered expression of key chondrogenic genes such as SOX9. These findings suggest that mechanical unloading disrupts the balance between matrix degradation and synthesis in chondrocytes. A study involving 12 astronauts who participated in 4- to 6-month missions aboard the ISS found that the absence of gravitational loading led to elevated urinary CTX-II (uCTX-II) levels, reflecting increased cartilage degradation⁴⁰. After 30 days of exposure to microgravity aboard a spaceflight vehicle, mice developed an osteoarthritis-like phenotype in the knee joint, suggesting that spaceflight may induce osteoarthritic changes in articular cartilage⁴¹. Although the cartilage degeneration observed in astronauts and flight animal experiments cannot be attributed solely to microgravity, the findings are consistent with the patterns observed in ground-based simulation studies.

Radiation

Radiation is one of the major hazardous factors in the space environment. During deep-space missions, astronauts are exposed to high-energy cosmic rays and solar particle events, and the cumulative radiation dose can affect multiple organs, including articular cartilage⁴². Kwok et al. ⁴³ demonstrated in a mouse model that even low-dose radiation can cause cartilage damage, characterized by reduced cartilage volume, accelerated degradation of type II collagen, and increased expression of the cartilage-degrading enzyme MMP-13. These findings are consistent with previously published studies⁴⁴. Radiation may accelerate cartilage degeneration, but further validation in humans is still required.

Although there is currently no direct clinical evidence of cartilage injury in astronauts, reports of joint damage and early-onset osteoarthritis in patients receiving radiation therapy for cancer provide indirect support for the potential risks associated with space radiation⁴⁵.

Hypoxia

Currently, the ISS operates under normobaric and normoxic conditions. However, future deep-space missions may adopt hypobaric and hypoxic environments to reduce the risk of decompression sickness during extravehicular activities⁴⁶.This shift in cabin atmosphere is particularly relevant to articular cartilage, an avascular tissue that naturally resides in a physiological hypoxic niche where low-oxygen tension supports chondrocyte homeostasis through hypoxia-inducible factor (HIF) signaling⁴⁷. In recent years, the role of HIFs in cartilage homeostasis has attracted increasing attention. HIFs are key transcription factors that regulate cellular adaptive responses to hypoxia, and in particular, HIF-1α has been identified as a crucial protective factor for articular cartilage. Studies have shown that chondrocytes are specialized to adapt to hypoxic environments by regulating tissue-specific metabolism through the HIFs pathway. This hypoxia-adaptive mechanism may provide potential protective effects for cartilage during future long-duration space missions⁴⁸.

The current ISS maintains a normobaric normoxic cabin atmosphere, allowing greater oxygen diffusion from synovial fluid and thereby producing relatively higher pericellular oxygen tension than the tissue’s deep-zone native hypoxic environment⁴². In contrast, future deep-space habitats may adopt hypobaric hypoxia, further lowering oxygen partial pressure and more strongly stabilizing HIF-1α and HIF-2α⁴⁹. Under ISS normoxia, prolyl hydroxylase domain enzymes (PHDs) remain active, driving HIF-α degradation and limiting cartilage-protective genes such as SOX9, type II collagen (COL2A1), and aggrecan (ACAN)⁵⁰. In hypobaric hypoxia, reduced oxygen inhibits PHD activity, leading to HIF-1α stabilization and nuclear accumulation, which shifts chondrocyte metabolism toward glycolysis while suppressing oxidative phosphorylation and ROS production⁵¹. HIF-2α, preferentially stabilized under sustained or moderate hypoxia, additionally drives SOX9-dependent extracellular matrix anabolism and chondrocyte differentiation, yet may exert context-dependent catabolic effects when hypoxia is severe or prolonged⁴⁷. Consequently, while normobaric normoxia on the ISS may offer limited metabolic adaptation to unloading, hypobaric hypoxia more closely recapitulates the native low-oxygen cartilage microenvironment and can enhance matrix synthesis and viability.

McDonnell et al.¹⁵ nvestigated 12 female participants who underwent three 10-day interventions: hypoxic ambulation, normoxic bed rest, and hypoxic bed rest. The results showed that serum COMP levels significantly decreased in the normoxic bed rest group but remained unchanged under hypoxic bed rest, while hypoxic activity appeared to increase cartilage metabolic turnover. These findings suggest that appropriate physical activity under hypoxic conditions may exert a protective effect on cartilage. Nevertheless, due to considerable baseline variability, further validation is required.

Elevated CO₂

Spacecraft operate under closed-loop life support systems, resulting in higher carbon dioxide (CO₂) concentrations inside the cabin compared with terrestrial environments⁵². Currently, direct evidence regarding the effects of elevated CO₂ on cartilage is limited. A human bed rest study conducted under simulated high-CO₂ conditions demonstrated increased bone resorption and suppressed bone formation, suggesting that alterations in the joint microenvironment may indirectly affect cartilage health⁵³.

Circadian rhythm disruption

Space missions often involve abnormal light–dark cycles, irregular work schedules, and frequent time zone shifts, leading to severe disruption of circadian rhythms in astronauts⁵⁴. Circadian rhythm–driven gene expression plays a crucial role in maintaining the metabolic balance and homeostasis of the cartilage matrix. Dudek et al.⁵⁵ reported that cartilage-specific deletion of BMAL1 in mice resulted in cartilage degeneration and reduced matrix synthesis, suggesting that BMAL1-mediated regulation of circadian gene expression is essential for cartilage homeostasis. Similarly, Naven et al.⁵⁶ found that during the differentiation of human embryonic stem cells into chondrocytes, rhythmic expression of core circadian clock genes, including BMAL1, PER2, and CLOCK genes was gradually established and correlated with cartilage maturation and matrix production. At the molecular level, articular cartilage maintains an autonomous peripheral clock governed by the core circadian genes BMAL1 and CLOCK. Under normal physiological conditions, this molecular clock strictly regulates tissue homeostasis by repressing the expression of key catabolic enzymes, notably the aggrecanases ADAMTS-4 and ADAMTS-5⁵⁵. Spaceflight-induced circadian dysregulation dampens BMAL1 expression, thereby lifting this repression and accelerating matrix degradation.

Psychological stress

Prolonged confinement, high workload, and potential hazards during space missions may contribute to psychological stress in astronauts. Chronic stress activates the hypothalamic–pituitary–adrenal (HPA) axis, leading to elevated glucocorticoid levels that exert catabolic effects on multiple tissues and may promote cartilage degradation⁵⁷. Animal studies have shown that psychological stress increases the levels of inflammatory cytokines, such as IL-1β and TNF-α, in articular cartilage, thereby promoting matrix degradation and inducing chondrocyte apoptosis⁵⁸. These findings suggest that psychological factors may influence cartilage health in astronauts. However, it should be noted that current evidence regarding the effects of psychological stress on articular cartilage is largely derived from animal and ground-based studies, and direct evidence from astronauts is still lacking. Therefore, the underlying mechanisms in the context of spaceflight remain speculative and require further validation in future studies.

Mechanisms underlying the effects of the space environment on articular cartilage

Mechanical unloading and matrix degradation

As the primary load-bearing tissue within joints, articular cartilage is highly sensitive to changes in mechanical loading. Throughout life, cartilage thickness and structure adapt to varying load conditions. For instance, the cartilage of the knee and hip joints, which are weight-bearing joints, is notably thicker than that of non–weight-bearing joints⁵⁹. Because articular cartilage is avascular, the exchange of nutrients and metabolic waste relies mainly on the flow of synovial fluid, which depends on regular joint motion. Appropriate mechanical activity promotes the removal of metabolic waste and the transport of nutrients within the cartilage, thereby maintaining chondrocyte viability and ECM homeostasis⁶⁰. Consequently, prolonged exposure to microgravity or physical inactivity can disrupt this balance, leading to adaptive cartilage degeneration.

The matrix of hyaline cartilage is primarily composed of PGs and type II collagen. PGs provide elasticity to the tissue, while collagen fibers form a network that ensures tensile strength. Alterations in these structural components collectively affect the mechanical stability of the cartilage and the viability of chondrocytes⁶¹. Therefore, when mechanical loading is absent, the synthesis and organization of these components are among the first to be disrupted. Nomura et al. observed that proteoglycan degradation increased after a period of mechanical unloading in tail-suspended mice⁶². Another study in rats found that mechanical unloading disrupted the balance between extracellular matrix synthesis and degradation, with catabolic processes predominating⁶³.

At the same time, the metabolic activity of chondrocytes is markedly reduced, as reflected by a diminished ability to synthesize PGs and type II collagen. This further exacerbates matrix degradation and accelerates degenerative changes in cartilage⁶⁰. Several studies have demonstrated that under mechanical unloading, the expression of matrix synthesis–related genes, such as COL2A1 and ACAN, is significantly decreased, whereas the expression of matrix degradation–related genes, including matrix metalloproteinase 13 (MMP-13) and ADAMTS-5, is markedly upregulated^63–65. These findings indicate that the absence of mechanical stimulation not only impairs anabolic pathways but also activates multiple catabolic enzyme–mediated degradation mechanisms.

During spaceflight-induced matrix turnover, the shift toward catabolism is further modulated by biological sex. A recent transcriptomic analysis of tissue-engineered human cartilage exposed to simulated microgravity demonstrated that female-derived chondrocytes exhibit a unique, specific upregulation of WNT7B and WNT9A within the Wnt signaling pathway⁶⁶. Because excessive Wnt/β-catenin signaling directly suppresses the synthesis of structural matrix proteins and accelerates the expression of matrix-degrading enzymes (such as aggrecanases), this female-specific pathway activation acts as a critical molecular driver, severely accelerating matrix catabolism and accelerating early osteoarthritis phenotypes in female crew members.

Molecular mechanosensors and chondrocyte responses to cartilage unloading

Articular chondrocytes sense mechanical unloading through cooperative gating of the mechanosensitive ion channels PIEZO1 and PIEZO2, which are synergistically activated by cyclic joint compression and fluid shear stress under normal gravity⁶⁷. In microgravity, the absence of dynamic loading markedly reduces PIEZO1/2 channel opening, thereby limiting Ca²⁺ influx that is essential for downstream anabolic signaling cascades⁶⁸. Reduced intracellular Ca²⁺ subsequently decreases CaMKII autophosphorylation and activity, preventing the phosphorylation events required for nuclear translocation of the transcriptional co-activators YAP and TAZ⁶⁹. Consequently, YAP/TAZ remain sequestered in the cytoplasm, directly suppressing the transcription of key cartilage matrix genes including ACAN and COL2A1 before overt extracellular matrix loss occurs⁷⁰. In parallel, primary cilia function as gravitational mechanosensors on the chondrocyte surface. Under microgravity or simulated unloading, rapid ciliary resorption occurs through microtubule depolymerization at the basal body⁷¹. This ciliary disassembly inactivates the BMP-2/Smad1/5/8 signaling axis, further contributing to early metabolic suppression and reduced matrix anabolism in the absence of detectable physical cartilage thinning⁷². Figure 1.

Fig. 1. Integrated mechanotransduction and biomarker kinetics of articular cartilage under spaceflight-induced unloading.

Under normal gravity (1G, left), cyclic mechanical loading activates PIEZO1/2 channels and primary cilia, leading to calcium influx, CaMKII activation, and nuclear translocation of YAP/TAZ to promote matrix anabolism (ACAN and COL2A). Under microgravity ($\mu$G, right), mechanical unloading inactivates these mechanosensors, resulting in CaMKII inactivation, YAP/TAZ cytoplasmic retention, and ciliary microtubule depolymerization, which collectively upregulate catabolic enzymes (MMP-13 and ADAMTS-4/5). The bottom timeline illustrates the progression of cartilage degeneration, transitioning from early reversible aggrecan depletion to sustained MMP elevation, and culminating in late irreversible structural damage characterized by peak urinary uCTX-II levels.

Oxidative stress and chondrocyte senescence

Exposure to space radiation and other environmental factors increases the generation of ROS, leading to oxidative stress in cartilage tissue. ROS can induce DNA damage and cause protein and lipid peroxidation, resulting in chondrocyte dysfunction and premature senescence⁷³. Typical hallmarks of chondrocyte senescence include increased senescence-associated β-galactosidase (SA-β-gal) activity and the senescence-associated secretory phenotype (SASP), characterized by elevated secretion of inflammatory and catabolic factors such as IL-6 and MMP-13, which drive ECM degradation and structural imbalance²⁶. Both in vivo and in vitro studies have demonstrated that ionizing radiation promotes chondrocyte senescence through a ROS-dependent p38 signaling pathway, accompanied by decreased sirtuin 1 (SIRT1) expression and amplification of SASP, thereby accelerating cartilage degeneration⁷⁴.

In addition, microgravity disrupts the balance between oxidative and antioxidative systems, as evidenced by decreased expression of the antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), along with reduced overall levels or activity of key antioxidant enzymes⁷³. Prolonged impairment of antioxidant enzyme function reduces the ability to eliminate ROS, making chondrocytes more vulnerable to oxidative damage⁷⁵.

Inflammation and immune activation

Inflammatory pathways are also involved in cartilage degeneration under space-related conditions. Both microgravity and radiation can activate the immune system and increase the expression of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis TNF-α in joint tissues⁴². These cytokines induce the upregulation of matrix-degrading enzymes, suppress anabolic signaling, and promote chondrocyte apoptosis. Animal studies have shown that the combination of mechanical unloading and radiation exacerbates synovial inflammation and cartilage erosion, accompanied by pronounced inflammatory cell infiltration in joint tissues⁶⁰. In addition, psychological stress can enhance the inflammatory microenvironment through elevated glucocorticoid levels and sympathetic nervous system activation, thereby accelerating cartilage degeneration.

Importantly, the magnitude of this spaceflight-induced joint inflammation exhibits significant sex dimorphism. Recent spaceflight multi-omic profiles from the SOMA atlas reveal that female astronauts demonstrate more robust innate immune and inflammatory responses to microgravity and radiation compared to males⁷⁶. Within the joint microenvironment, female-derived chondrocytes and synovial macrophages exhibit a more pronounced upregulation of proinflammatory cytokines, notably IL-6 and TNF-α, upon mechanical unloading⁷⁷. Furthermore, spaceflight-induced alterations in estrogen receptor signaling can compromise the baseline anti-inflammatory protection typically afforded by estrogen in females, thereby predisposing the joint to an accelerated inflammatory cascade during long-duration missions⁷⁸.

Countermeasures against articular cartilage degeneration

Exercise intervention and mechanical stimulation

To mitigate the cartilage degeneration induced by prolonged mechanical unloading, various exercise interventions and mechanical stimulation strategies have been explored. Liphardt et al. ⁷⁹ found that in healthy adults, exercise substitution training could not counteract the cartilage biomarker response induced by five days of immobilization. In another study, Liphardt et al. ²³ reported that physical exercise intervention during bed rest, consisting of whole-body vibration without additional resistance training, failed to prevent the immobilization-induced reduction in serum COMP after 14 days of bed rest. An animal study demonstrated that intermittent high-impact loading effectively counteracted cartilage thinning induced by unloading and improved bone mineral density. These findings suggest that simulated jump or impact training devices may help protect cartilage⁸⁰, although the optimal intensity and frequency parameters require further investigation.

In addition, artificial gravity generated by short-arm centrifugation has been proposed as a potential countermeasure for spaceflight-induced disorders and may help restore joint loading directly, although its efficacy remains to be verified⁸¹. Wearable devices such as the Skinsuit (Gravity Loading Countermeasure Suit, GLCS) and Russia’s Pingvin Suit apply axial traction to simulate approximately 0.07–0.7 g of gravitational load. While preliminary evidence supports their effectiveness in mitigating spinal deconditioning, their direct protective effects on lower limb articular cartilage have not yet been evaluated⁸².

To maximize the efficacy of physical interventions, future protocols must evolve to incorporate ‘chrono-countermeasures.’ By precisely aligning exercise and mechanical loading with the chondrocytes’ inherent daily anabolic peaks, astronauts can effectively entrain and stabilize the peripheral cartilage clock. This temporal alignment ensures that therapeutic stimuli are delivered when the tissue is most receptive to anabolic signaling, thereby optimizing joint protection and delaying matrix degradation during long-duration spaceflight⁸³.

Pharmacological and nutritional approaches

Kartogenin (KGN), a potential “exercise-mimetic” compound, has been shown to promote the expression of ACAN, COL2A1, and SOX9, as well as ECM production, thereby enhancing chondrogenic differentiation, cartilage protection, and repair in mesenchymal stem cell (MSC) scaffold cultures and animal models. However, because KGN has not yet been tested in clinical trials, further studies are required to confirm its biosafety and efficacy⁸⁴. While small molecules like KGN show great promise in promoting chondrogenesis, their effective delivery into dense, avascular cartilage remains a clinical challenge. To resolve this, advanced and flight-feasible delivery systems, such as Janus Base Nanomaterials (JBNs), should be integrated. Recent spaceflight experiments indicate that these DNA-inspired JBNs achieve increased structural uniformity and enhanced self-assembly when manufactured in microgravity⁸⁵. Consequently, these microgravity-optimized JBNs can serve as highly efficient delivery vehicles for KGN, ensuring targeted cartilage regeneration without the logistical constraints of cold-chain storage during deep-space missions.

Glucosamine and chondroitin sulfate have demonstrated anabolic and anti-degradative properties with favorable safety profiles, although substantial interindividual variability in treatment response has been reported⁸⁶. Omega-3 fatty acids and magnesium, due to their anti-inflammatory and mineral regulatory functions, are also considered to provide adjunctive protection for cartilage^87,88. Liphardt et al. ⁸⁹ demonstrated that nutritional countermeasures, including whey protein and bicarbonate supplementation, did not affect serum concentrations of cartilage biomarkers. Furthermore, a critical clinical conflict exists in the systemic management of spaceflight-induced musculoskeletal loss due to bone-cartilage crosstalk. While sclerostin inhibitors are highly effective at mitigating microgravity-induced bone density loss by promoting osteoblast Wnt signaling, their impact on adjacent articular cartilage can be detrimental^90,91. Sclerostin naturally acts as a protective molecule within the joint by inhibiting Wnt-dependent catabolic enzymes (such as MMPs) and preventing abnormal mineralization. Consequently, systemic pharmacological inhibition of sclerostin can lead to a pathological overactivation of Wnt signaling in the joint compartment, potentially triggering subchondral bone hypertrophy and osteophyte formation⁹⁰. To mitigate these joint risks while preserving bone mass, future countermeasure protocols must explore localized drug delivery systems or dual-targeting therapies that can effectively decouple bone anabolism from cartilage catabolism.

Radiation protection

Radiation protection can be achieved through several approaches, such as direct shielding using materials like aluminum alloys and polyethylene^92,93.Pharmacological strategies also provide a potential means of protection. Antioxidants can help mitigate oxidative damage caused by high-charge and high-energy particles⁹⁴, while radioprotective agents and gene repair drugs may offer additional protective effects⁹⁵.

Other therapeutic approaches

Low-Intensity Pulsed Ultrasound (LIPUS) is a highly flight-feasible option for long-duration missions. Unlike bulky mechanical loading devices, LIPUS units are portable and non-invasive, capable of providing essential mechanical-like stimulation to chondrocytes to preserve matrix integrity through non-thermal acoustic effects⁹⁶. Multiple animal and clinical studies have demonstrated that LIPUS promotes chondrocyte proliferation and activates SOX9, thereby upregulating the expression of COL2A1 and ACAN. In addition, LIPUS inhibits IL-1β/NF-κB activation and MMP-13 expression, suppresses apoptosis, and enhances ECM synthesis and tissue repair^97–99. Table 2.

Table 2.

Effects of space-related stressors on articular cartilage

Stressor	Primary Effect on Cartilage	Key Mechanisms	Key Biomarkers	Potential Countermeasures
Microgravity	Mechanical unloading → matrix catabolism	↓ PIEZO1/2-Ca²⁺-CaMKII-YAP/TAZ; ciliary resorption → ↓ BMP-2/Smad	↑ MMP-1/13, ↑ uCTX-II, ↓ COMP	Exercise, Nutritional intervention, LIPUS
Radiation	Oxidative stress → chondrocyte senescence	↑ ROS → p38 → SASP; DNA damage	↑ MMP-13, ↑ SA-β-gal	Shielding, antioxidants
Hypoxia (hypobaric)	Differential HIF signaling	↑ HIF-1α/2α → glycolysis vs. normoxia	Variable COMP; HIF target genes	Oxygen control, HIF modulators
Elevated CO₂	Indirect via bone resorption	Altered joint microenvironment	↑ Bone resorption markers	Ventilation optimization
Circadian disruption	Peripheral clock desynchronization	↓ BMAL1/CLOCK → ↑ ADAMTS-4/5	Disrupted rhythmic gene expression	Timed exercise
Psychological stress	Inflammation & catabolism	↑ Glucocorticoids → IL-1β/TNF-α	↑ IL-6, ↑ MMPs	Stress management

Conclusion

In the space environment, multiple factors, including microgravity, radiation, hypoxia, elevated CO₂, circadian rhythm disruption, and psychological stress, act synergistically to threaten the structural and functional integrity of astronauts’ articular cartilage. The core mechanism involves a significant reduction in mechanical loading under weightlessness, accompanied by metabolic and molecular dysregulation across multiple pathways.

To ensure the protection of joint health during future missions, several critical research gaps must be addressed. First, direct cartilage imaging or biopsy data from astronauts during or immediately after spaceflight are currently unavailable; future missions could consider incorporating validated in-flight biomarker monitoring protocols, including urinary CTX-II (uCTX-II) and serum COMP, to establish mission-duration dose–response relationships. Second, the majority of existing studies have used male-only or mixed-sex cohorts without sex-stratified analyses; given the potential for sex-specific cartilage responses, future research should explicitly incorporate sex as a biological variable. Third, the long-term recovery trajectory of cartilage after return from extended missions remains poorly defined, and longitudinal post-flight studies are urgently needed to determine whether mission-induced changes are fully reversible. Finally, since the protective efficacy of current interventions remains to be fully validated, the development and spaceflight qualification of flight-compatible therapeutic devices should be prioritized as part of optimized, integrated countermeasure programs for future deep-space exploration.

Author contributions

Z.R. conducted the literature review and drafted the manuscript. H.H. and J.W. critically reviewed and revised the manuscript. All authors approved the final version of the paper.

Data availability

No datasets were generated or analysed during the current study.

Competing interests

The authors declare no competing interests.