Response Of Cartilage Research Articles

Disuse atrophy of articular cartilage can be restored by mechanical reloading in mice

BackgroundModerate mechanical stress generated by normal joint loading and movements helps maintain the health of articular cartilage. Despite growing interest in the pathogenesis of cartilage degeneration caused by reduced mechanical stress, its reversibility by mechanical reloading is less understood. This study aimed to investigate the response of articular cartilage exposed to mechanical reloading after unloading in vivo and in vitro.Methods and resultsDisuse atrophy was induced in the knee joint cartilage of adult mice through hindlimb unloading by tail suspension. For in vivo experiments, mice were subjected to reloading with or without daily exercise intervention or surgical destabilization of the knee joint. Microcomputed tomography and histomorphometric analyses were performed on the harvested knee joints. Matrix loss and thinning of articular cartilage due to unloading were fully or partially restored by reloading, and exercise intervention enhanced the restoration. Subchondral bone density decreased by unloading and increased to above-normal levels by reloading. The severity of cartilage damage caused by joint instability was not different even with prior non-weight bearing. For in vitro experiments, articular chondrocytes isolated from the healthy or unloaded joints of the mice were embedded in agarose gel. After dynamic compression loading, the expression levels of anabolic (Sox9, Col2a1, and Acan) and catabolic (Mmp13 and Adamts5) factors of cartilage were analyzed. In chondrocytes isolated from the unloaded joints, similar to those from healthy joints, dynamic compression increased the expression of anabolic factors but suppressed the expression of catabolic factors.ConclusionThe results of this study indicate that the morphological changes in articular cartilage exposed to mechanical unloading may be restored in response to mechanical reloading by shifting extracellular matrix metabolism in chondrocytes to anabolism.

Articular cartilage fatigue causes frequency-dependent softening and crack extension

Soft biological polymers, such as articular cartilage, possess exceptional fracture and fatigue resistance, offering inspiration for the development of novel materials. However, we lack a detailed understanding of changes in cartilage material behavior and of crack propagation following cyclic compressive loading. We investigated the structure and mechanical behavior of cartilage as a function of loading frequency and number of cycles. Microcracks were initiated in cartilage samples using microindentation, then cracks were extended under cyclic compression. Thickness, apparent stiffness, energy dissipation, phase angle, and crack length were measured to determine the effects of cyclic loading at two frequencies (1 Hz and 5 Hz). To capture the fatigue-induced material response (thickness, stiffness, energy dissipation, and phase angle), material properties were compared between pre-and-post diagnostic tests. The findings indicate that irreversible structural damage (reduced thickness), cartilage softening (reduced apparent stiffness), and reduced energy dissipation (including phase angle) increased with an increase in the number of cycles. Higher frequency loading resulted in less reduction in energy dissipation, phase angle, and thickness change. Crack lengths, quantified through brightfield imaging, increased with number of cycles and frequency. This study sheds light on the complex response of cartilage under cyclic loading resulting in softening, structural damage, and altered dynamic behavior. The findings provide better understanding of failure mechanisms in cartilage and thus may help in diagnosis and treatment of osteoarthritis.

Synovial fluid does not retard fluid exudation during stress-relaxation of immature bovine cartilage

Interstitial fluid load support (FLS) is a dominant mechanism of lubrication in cartilage, producing a low friction coefficient while enhancing the tissue’s load bearing capabilities. Due to its viscosity, synovial fluid (SF) may retard loss of FLS by slowing the exudation of interstitial fluid from the cartilage. This study tested this hypothesis by comparing the stress-relaxation (SRL) response of immature bovine articular cartilage immersed either in phosphate buffered saline (PBS) or in healthy mature bovine SF, under unconfined compression (fluid exudation across cut lateral tissue boundary) and indentation testing (fluid exudation across articular surface). To investigate the influence of diffusion of SF molecular constituents into cartilage, the effect of incubation time in SF on SRL was also investigated. The SRL response in unconfined compression was not significantly different in PBS versus SF when compared directly (p = 0.98) and had a slope ofm = 1.00 ± 0.04 (R2 = 0.989 ± 0.007). Samples tested in PBS exhibited characteristic relaxation times, τPBS=42.6 ± 5.3 s andτSF = 40.8 ± 4.7 s, that were not significantly different (p = 0.40). Incubation time of 24 h in SF resulted in no significant difference in the SRL response (p = 0.39, m=1.03 ± 0.12; R2=0.983 ± 0.011, andτPBS = 43.4 ± 10.7 s versusτSF = 41.5 ± 4.8 s, p = 0.59). Indentation testing showed some statistically significant, but functionally insignificant, difference in SRL responses in PBS versus SF with a slope ofm = 0.958 ± 0.060 (R2 = 0.957 ± 0.020, p = 0.029, andτPBS = 16.9 ± 2.6 s versusτSF = 19.4 ± 3.3 s, p = 0.073). Based on these results, we reject the hypothesis that healthy SF can retard the loss of FLS in cartilage due to its viscosity.

Evaluation of the impact of ultra-trail running on knee cartilage using magnetic resonance imaging t2 mapping.

Ultra-marathon trails involve a combination of specific physiological and mechanical constraints and raise new questions regarding the osteoarticular impact on the knees and the long-term risk of osteoarthritis. Magnetic resonance imaging (MRI) T2 relaxation time measurement has shown the ability to determine cartilage response to loading. Higher T2 measurements correspond with cartilage damage. The aim of this study was to quantify the changes in MRI T2 relaxation times of knee articular cartilage after an ultra-trail run and determine knee's consequences of regular practice. Twenty participants in a 55-km race involving total elevation changes of 2600m had 1.5-T knee MRI prior to the race (V0), immediately after (V1) and one month after the race (V2) for T2 relaxation times measurement and morphological sequences (T1, T2 & T2 Fast-Spin Echo (FSE)). T2 measurements were significantly increased in V1 from V0 and remained so one month after the race (V2), despite a significant reduction from V1. Morphological sequences revealed that 65% of the participant had cartilage damage and 65% meniscal damage, 100% of which affected the posterior horn of the medial meniscus. Only one subject (5%) presented no anomaly whatsoever. Damage appeared to be stable between the assessments. Ultra-trail running leads to modifications in the knee cartilage ultrastructure, which persists for at least one month after the event. Furthermore, regular ultra-trail runners present a high number of low-grade cartilage and meniscus lesions.

Morphologic Response in Femoral Cartilage During and After 40-Minute Treadmill Running.

It is unclear whether the response in femoral cartilage to running at different intensities is different. To examine the acute patterns of deformation and recovery in femoral cartilage thickness during and after running at different speeds. Crossover study. Laboratory. A total of 17 healthy men (age = 23.9 ± 2.3 years, height = 173.1 ± 5.5 cm, mass = 73.9 ± 8.0 kg). Participants performed a 40-minute treadmill run at speeds of 7.5 and 8.5 km/h. Ultrasonographic images of femoral cartilage thickness (intercondylar, lateral condyle, and medial condyle) were obtained every 5 minutes during the experiment (40 minutes of running followed by a 60-minute recovery period) at each session. Data were analyzed using analysis of variance and Bonferroni- and Dunnett-adjusted post hoc t tests. To identify patterns of cartilage response, we extracted principal components (PCs) from the cartilage-thickness data using PC analysis, and PC scores were analyzed using t tests. Regardless of time, femoral cartilage thicknesses were greater for the 8.5-km/h run than the 7.5-km/h run (intercondylar: F1,656 = 24.73, P < .001, effect size, 0.15; lateral condyle: F1,649 = 16.60, P < .001, effect size, 0.16; medial condyle: F1,649 = 16.55, P < .001, effect size, 0.12). We observed a time effect in intercondylar thickness (F20,656 = 2.15, P = .003), but the Dunnett-adjusted post hoc t test revealed that none of the time point values differed from the baseline value (P > .38 for all comparisons). Although the PC1 and PC2 captured the magnitudes of cartilage thickness and time shift (eg, earlier versus later response), respectively, t tests showed that the PC scores were not different between 7.5 and 8.5 km/h (intercondylar: P ≥ .32; lateral condyle: P ≥ .78; medial condyle: P ≥ .16). Although the 40-minute treadmill run with different speeds produced different levels of fatigue, morphologic differences (<3%) in the femoral cartilage at both speeds seemed to be negligible.

Characterizing and Modeling Ovine Hide and Costal Cartilage for Use in Modeling High-Rate Non-Penetrating Blunt Impact.

High-rate non-penetrating blunt impacts to the thorax, such as from impacts to protective equipment, can lead to a wide range of thoracic injuries. These injuries can include rib fractures, lung contusions, and abdominal organ contusions. Ovine animals have been used to study such impacts, in a variety of ways, including in silico. To properly model these impacts in silico, it is imperative that the tissues impacted are properly characterized. The objective of this study is to characterize and validate two tissues impacted that are adjacent to the point of impact-costal cartilage and hide. Heretofore, these materials have not been characterized for use in computational models despite their nearly immediate engagement in the high-rate, non-penetrating loading environment. Ovine costal cartilage and hide samples were procured from a local abattoir following USDA regulations. Costal cartilage samples were then cut into ASTM D638 Type V tensile coupons and compressive disks for testing. The cartilage tensile coupons were tested at 150 ε/s, and the compressive samples were tested at -150 ε/s. Identical coupons and disks were then simulated in LS-Dyna using a hyperelastic material model based on test data and experimental boundary conditions. Hide samples were shaved and cut into ASTM D638 Type V tensile coupons and validated in silico using identical boundary conditions and an Ogden rubber model based on test data. The structural responses of costal cartilage and hide are presented and exhibit typical behavior for biological specimens. The respective model fits in LS-Dyna were a hyperelastic- based "simplified rubber" for the costal cartilage and an Ogden rubber for the hide. The costal cartilage had a mean failure strain of 0.094 ± 0.040 in tension and -0.1755 ± 0.0642 in compression. The costal cartilage was also noted to have an order-of-magnitude difference in the stresses observed experimentally between the tensile and compressive experiments. Hide had a mean failure strain of 0.2358 ± 0.1362. The energies for all three simulations showed material stability. Overall, we successfully characterized the mechanical behavior of the hide and costal cartilage in an ovine model. The data are intended for use in computational analogs of the ovine model for testing non-penetrating blunt impact in silico. To improve upon these models, rate sensitivity should be included, which will require additional mechanical testing.

Chondrocyte Response to Fresh Autologous Conditioned Serum Versus Freeze-Dried Allogenic Conditioned Serum.

To investigate the cytokine release profile and histological response of human cartilage after exposure to autologous conditioned serum (ACS) and freeze-dried allogenic conditioned serum (FD-CS). Cartilage explants were collected from 6 patients undergoing total knee arthroplasty. ACS and FD-CS were created from patient serum samples. Cartilage samples were divided into 6 groups: (1) untreated control, (2) ACS, (3) FD-CS, (4) untreated interleukin (IL)-1β (5 ng/ml), (5) IL-1β + ACS, and (6) IL-1β + FD-CS. After 12 days, cartilage samples were analyzed with glycosaminoglycan (GAG) concentration normalized to wet weight while comparing cytokine concentrations, and histological scoring. There was a significant decrease in pathology scoring for ACS (P = 0.0368) and FD-CS (P = 0.0368) in the IL-1β injury groups compared with the untreated IL-1β insult group. ACS and FD-CS significantly mitigate the IL-1β induced increase in basic fibroblast growth factor (bFGF) (P = 0.0009 and P = 0.0002, respectively). FD-CS showed a significant decrease in IL-1β concentration in the presence of IL-1β insult compared with the untreated IL-1β group (P < 0.0001). ACS-treated samples had significantly higher concentration of tumor necrosis factor (TNF)-α independent of IL-1β when compared with samples not treated with biologics (P = 0.0053). Explanted osteoarthritic cartilage responds favorably and equivalently to treatment with ACS and FD-CS from a histological perspective. Both ACS and FD-CS were able to mitigate the IL-1β-induced increases in bFGF and FD-CS lowered IL-1β concentration while increasing interleukin-1 receptor antagonist (IL-1Ra) concentration. Although the cytokine profile of cartilage tissue explants treated with FD-CS appears to be different than that of ACS, this difference does not seem to affect biologic activity of FD-CS.

Loss of β-arrestin2 aggravated condylar cartilage degeneration at the early stage of temporomandibular joint osteoarthritis

ObjectiveTemporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative joint disorder characterized by extracellular matrix degeneration and inflammatory response of condylar cartilage. β-arrestin2 is an important regulator of inflammation response, while its role in TMJOA remains unknown. The objective of this study was to investigate the role of β-arrestin2 in the development of TMJOA at the early stage and the underlying mechanism.MethodsA unilateral anterior crossbite (UAC) model was established on eight-week-old wild-type (WT) and β-arrestin2 deficiency mice to simulate the progression of TMJOA. Hematoxylin-eosin (HE) staining and microcomputed tomography (micro-CT) analysis were used for histological and radiographic assessment. Immunohistochemistry was performed to detect the expression of inflammatory and degradative cytokines, as well as autophagy related factors. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay was carried out to assess chondrocyte apoptosis.ResultsThe loss of β-arrestin2 aggravated cartilage degeneration and subchondral bone destruction in the model of TMJOA at the early stage. Furthermore, in UAC groups, the expressions of degradative (Col-X) and inflammatory (TNF-α and IL-1β) factors in condylar cartilage were increased in β-arrestin2 null mice compared with WT mice. Moreover, the loss of β-arrestin2 promoted apoptosis and autophagic process of chondrocytes at the early stage of TMJOA.ConclusionIn conclusion, we demonstrated for the first time that β-arrestin2 plays a protective role in the development of TMJOA at the early stage, probably by inhibiting apoptosis and autophagic process of chondrocytes. Therefore, β-arrestin2 might be a potential therapeutic target for TMJOA, providing a new insight for the treatment of TMJOA at the early stage.

Sensitivity of cartilage mechanical behaviour to spatial variations in material properties

Articular cartilage tissue exhibits a spatial dependence in material properties that govern mechanical behaviour. A mathematical model of cartilage tissue under one dimensional confined compression testing is developed for normal tissue that takes account of these variations in material properties. Modifications to the model representative of a selection of mechanisms driving osteoarthritic cartilage are proposed, allowing application of the model to both physiological and pathophysiological, osteoarthritic tissue. Incorporating spatial variations into the model requires the specification of more parameters than are required in the absence of these variations. A global sensitivity analysis of these parameters is implemented to identify the dominant mechanisms of mechanical response, in normal and osteoarthritic cartilage tissue, to both static and dynamic loading. The most sensitive parameters differ between dynamic and static mechanics of the cartilage, and also differ between physiological and osteoarthritic pathophysiological cartilage. As a consequence changes in cartilage mechanics in response to alterations in cartilage structure are predicted to be contingent on the nature of loading and the health, or otherwise, of the cartilage. In particular the mechanical response of cartilage, especially deformation, is predicted to be much more sensitive to cartilage stiffness in the superficial zone given the onset of osteoarthritic changes to material properties, such as superficial zone increases in permeability and reductions in fixed charge. In turn this indicates that any degenerative changes in the stiffness associated with the superficial cartilage collagen mesh are amplified if other elements of osteoarthritic disease are present, which provides a suggested mechanism-based explanation for observations that the range of mechanical parameters representative of normal and osteoarthritic tissue can overlap substantially.

Micro-current stimulation could inhibit IL-1β-induced inflammatory responses in chondrocytes and protect knee bone cartilage from osteoarthritis.

This study aimed to evaluate the inhibitory effects of micro-current stimulation (MCS) on inflammatory responses in chondrocytes and degradation of extracellular matrix (ECM) in osteoarthritis (OA). To determine the efficacy of MCS, IL-1β-treated chondrocytes and monosodium iodoacetate (MIA)-induced OA rat model were used. To evaluate the cytotoxicity and nitric oxide (NO) production in SW1353 cells, the presence or absence of IL-1β treatment or various levels of MCS were applied. Immunoblot analysis was conducted to evaluate whether MCS can modulate IL-1R1/MyD88/NF-κB signaling pathway and various indicators involved in ECM degradation. Additionally, to determine whether MCS alleviates subchondral bone structure destruction caused by OA, micro-CT analysis, immunoblot analysis, and ELISA were conducted using OA rat model. 25 and 50 µA levels of MCS showed effects in cell proliferation and NO production. The MCS group with IL-1β treatment lead to significant inhibition of protein expression levels regarding IL-1R1/MyD88/NF-κB signaling and reduction of the nucleus translocation of NF-κB. In addition, the protein expression levels of MMP-1, MMP-3, MMP-13, and IL-1β decreased, whereas collagen II and aggrecan increased. In animal results, morphological analysis of subchondral bone using micro-CT showed that MCS induced subchondral bone regeneration and improvement, as evidenced by increased thickness and bone mineral density of the subchondral bone. Furthermore, MCS-applied groups showed decreases in the protein expression of MMP-1 and MMP-3, while increases in collagen-II and aggrecan expressions. These findings suggest that MCS has the potential to be used as a non-pharmaceutical method to alleviate OA.

Biomechanics of the Human Osteochondral Unit: A Systematic Review.

The damping system ensured by the osteochondral (OC) unit is essential to deploy the forces generated within load-bearing joints during locomotion, allowing furthermore low-friction sliding motion between bone segments. The OC unit is a multi-layer structure including articular cartilage, as well as subchondral and trabecular bone. The interplay between the OC tissues is essential in maintaining the joint functionality; altered loading patterns can trigger biological processes that could lead to degenerative joint diseases like osteoarthritis. Currently, no effective treatments are available to avoid degeneration beyond tissues' recovery capabilities. A thorough comprehension on the mechanical behaviour of the OC unit is essential to (i) soundly elucidate its overall response to intra-articular loads for developing diagnostic tools capable of detecting non-physiological strain levels, (ii) properly evaluate the efficacy of innovative treatments in restoring physiological strain levels, and (iii) optimize regenerative medicine approaches as potential and less-invasive alternatives to arthroplasty when irreversible damage has occurred. Therefore, the leading aim of this review was to provide an overview of the state-of-the-art-up to 2022-about the mechanical behaviour of the OC unit. A systematic search is performed, according to PRISMA standards, by focusing on studies that experimentally assess the human lower-limb joints' OC tissues. A multi-criteria decision-making method is proposed to quantitatively evaluate eligible studies, in order to highlight only the insights retrieved through sound and robust approaches. This review revealed that studies on human lower limbs are focusing on the knee and articular cartilage, while hip and trabecular bone studies are declining, and the ankle and subchondral bone are poorly investigated. Compression and indentation are the most common experimental techniques studying the mechanical behaviour of the OC tissues, with indentation also being able to provide information at the micro- and nanoscales. While a certain comparability among studies was highlighted, none of the identified testing protocols are currently recognised as standard for any of the OC tissues. The fibril-network-reinforced poro-viscoelastic constitutive model has become common for describing the response of the articular cartilage, while the models describing the mechanical behaviour of mineralised tissues are usually simpler (i.e., linear elastic, elasto-plastic). Most advanced studies have tested and modelled multiple tissues of the same OC unit but have done so individually rather than through integrated approaches. Therefore, efforts should be made in simultaneously evaluating the comprehensive response of the OC unit to intra-articular loads and the interplay between the OC tissues. In this regard, a multidisciplinary approach combining complementary techniques, e.g., full-field imaging, mechanical testing, and computational approaches, should be implemented and validated. Furthermore, the next challenge entails transferring this assessment to a non-invasive approach, allowing its application in vivo, in order to increase its diagnostic and prognostic potential.

Response of Articular Cartilage to Hyperosmolar Stress: Report of an Ex Vivo Injury Model

Background: Physiological 0.9% saline is commonly used as an irrigation fluid in modern arthroscopy. There is a growing body of evidence that a hyperosmolar saline solution has chondroprotective effects, especially if iatrogenic injury occurs. Purpose: To (1) corroborate the superiority of a hyperosmolar saline solution regarding chondrocyte survival after mechanical injury and (2) observe the modulatory response of articular cartilage to osmotic stress and injury. Study Design: Controlled laboratory study. Methods: Osteochondral explants were isolated from bovine stifle joints and exposed to either 0.9% saline (308 mOsm) or hyperosmolar saline (600 mOsm) and then damaged with a sharp dermatome blade to attain a confined full-thickness cartilage injury site, incubated in the same fluids for another 3 hours, and transferred to chondropermissive medium for further culture for 1 week. Chondrocyte survival was assessed by confocal imaging, while the cellular response was evaluated over 1 week by relative gene expression for apoptotic and inflammatory markers and mediator release into the medium. Results: The full-thickness cartilage cut resulted in a confined zone of cell death that mainly affected superficial zone chondrocytes. Injured samples that were exposed to hyperosmolar saline showed less expansion of cell death in both the axial (P < .007) and the coronal (P < .004) plane. There was no progression of cell death during the following week of culture. Histological assessment revealed an intact cartilage matrix and normal chondrocyte morphology. Inflammatory and proapoptotic genes were upregulated on the first days postexposure with a notable downregulation toward day 7. Mediator release into the medium was concentrated on day 3. Conclusion: This in vitro cartilage injury model provides further evidence for the chondroprotective effect of a hyperosmolar saline irrigation fluid, as well as novel data on the capability of articular cartilage to quickly regain joint homeostasis after osmotic stress and injury. Clinical Relevance: Raising the osmolarity of an irrigating solution may be a simple and safe strategy to protect articular cartilage during arthroscopic surgery.

Characterization of the invivo transient responses of the femoral cartilage by means of quantitative ultrasound imaging techniques.

Quantitative ultrasound (QUS) techniques are new diagnostic tools able to identify changes in structural and material properties of the investigated tissue. For the first time, we evaluated the capability of QUS techniques in determining the invivo transient changes in knee joint cartilage after a stressful task. An ultrasound scanner collecting B-mode and radiofrequency data simultaneously was used to collect data from the femoral cartilage of the right knee in 15 participants. Cartilage thickness (CTK), ultrasound roughness index (URI), average magnitude ratio (AMR), and Nakagami parameters (NA) were evaluated before, immediately after and every 5 min up to 45 min a stressful task (30 min of running on a treadmill with a negative slope of 5%). CTK was affected by time (main effect: p < 0.001). Post hoc test showed significant differences with CTK at rest, which were observed up to 30 min after the run. AMR and NA were affected by time (p < 0.01 for both variables), while URI was unaffected by it. For AMR, post hoc test showed significant differences with rest values in the first 35 min of recovery, while NA was increased compared to rest values in all time points. Data suggest that a single running trial is not able to modify the integrity of the femoral cartilage, as reported by URI data. Invivo evaluation of QUS parameters of the femoral cartilage (NA, AMR, and URI) are able to characterize changes in cartilage properties over time.

In Situ Loading and Time-Resolved Synchrotron-Based Phase Contrast Tomography for the Mechanical Investigation of Connective Knee Tissues: A Proof-of-Concept Study.

Articular cartilage and meniscus transfer and distribute mechanical loads in the knee joint. Degeneration of these connective tissues occurs during the progression of knee osteoarthritis, which affects their composition, microstructure, and mechanical properties. A deeper understanding of disease progression can be obtained by studying them simultaneously. Time-resolved synchrotron-based X-ray phase-contrast tomography (SR-PhC-µCT) allows to capture the tissue dynamics. This proof-of-concept study presents a rheometer setup for simultaneous in situ unconfined compression and SR-PhC-µCT of connective knee tissues. The microstructural response of bovine cartilage (n = 16) and meniscus (n = 4) samples under axial continuously increased strain, or two steps of 15% strain (stress-relaxation) is studied. The chondrocyte distribution in cartilage and the collagen fiber orientation in the meniscus are assessed. Variations in chondrocyte density reveal an increase in the top 40% of the sample during loading, compared to the lower half. Meniscus collagen fibers reorient perpendicular to the loading direction during compression and partially redisperse during relaxation. Radiation damage, image repeatability, and image quality assessments show little to no effects on the results. In conclusion, this approach is highly promising for future studies of human knee tissues to understand their microstructure, mechanical response, and progression in degenerative diseases.

The role of monocyte/macrophage chemokines in pathogenesis of osteoarthritis: A review.

Osteoarthritis (OA) is one of the most common degenerative diseases characterised by joint pain, swelling and decreased mobility, with its main pathological features being articular synovitis, cartilage degeneration and osteophyte formation. Inflammatory cytokines and chemokines secreted by activated immunocytes can trigger various inflammatory and immune responses in articular cartilage and synovium, contributing to the genesis and development of OA. A series of monocyte/macrophage chemokines, including monocyte chemotaxis protein (MCP)-1/CCL2, MCP2/CCL8, macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, MIP-3α/CCL20, regulated upon activation, normal T-cell expressed and secreted /CCL5, CCL17 and macrophage-derived chemokine/CCL22, was proven to transmit cell signals by binding to G protein-coupled receptors on recipient cell surface, mediating and promoting inflammation in OA joints. However, the underlying mechanism of these chemokines in the pathogenesis of OA remains still elusive. Here, published literature was reviewed, and the function and mechanisms of monocyte/macrophage chemokines in OA pathogenesis were summarised. The symptoms and disease progression of OA were found to be effectively alleviated when the expression of these chemokines is inhibited. Elucidating these mechanisms could contribute to further understand how OA develops and provide potential targets for the early diagnosis of arthritis and drug treatment to delay or even halt OA progression.

Characteristics of Acute Cartilage Response After Mechanical Loading in Patients with Early-Mild Knee Osteoarthritis.

This study determined whether the acute cartilage response, assessed by cartilage thickness and echo intensity, differs between patients with early-mild knee osteoarthritis (OA) and healthy controls. We recruited 56 women aged ≥ 50years with Kellgren-Lawrence (KL) grade ≤ 2 (age, 70.6 ± 7.4years; height, 153.7 ± 5.2cm; weight, 51.9 ± 8.2kg). Based on KL grades and knee symptoms, the participants were classified into control (KL ≤ 1, asymptomatic, n = 27) and early-mild knee OA groups (KL 1 and symptomatic, KL 2, n = 29). Medial femoral cartilage thickness and echo intensity were assessed using ultrasonographic B-mode images before and after treadmill walking (15min, 3.3km/h). To investigate the acute cartilage response, repeated-measures analysis of covariance (groups × time) with adjusted age, external knee moment impulse, steps during treadmill walking, and cartilage thickness at pre-walking was performed. A significant interaction was found at the tibiofemoral joint; after walking, the cartilage thickness was significantly decreased in the early-mild knee OA group compared to the control group (p = 0.002). At the patellofemoral joint, a significant main effect of time was observed, but no interaction was detected (p = 0.802). No changes in cartilage echo intensity at either the tibiofemoral or patellofemoral joints, and no interactions were noted (p = 0.295 and p = 0.063). As acute cartilage response after walking, the thickness of the medial tibiofemoral joint in the early-mild knee OA was significantly reduced than that in the control group. Thus, greater acute deformation after walking might be a feature found in patients with early-mild knee OA.

A NEW CRITERION FOR THE HUMAN KNEE OSTEOARTHRITIS CHARACTERIZATION: FINITE-ELEMENT MODELING

Osteoarthritis (OA), characterized by the degradation of articular cartilage, is a musculoskeletal disease that occurs as the result of variations in the mechanical stress and strain applied to the knee joint. Since damaged cartilage has very poor intrinsic repair and regenerative capacity, numerical modeling complemented by experimental studies have been widely investigated to examine the causes of OA development. However, the responses of the articular cartilage to a load distributed as a function of knee laxity in the frontal plane have not been studied numerically. Accordingly, we provide in this paper a 3D finite-element (FE) model of the knee joint obtained from magnetic resonance imaging (MRI) dataset, in order to assess the biomechanical responses of cartilage. The main goal of this work is to develop a new methodology to quantify the load applied to the knee and to propose a new criterion for characterizing cartilage wear based on arthroscopic and radiological classifications. In the situations of varus and valgus laxity, the FE analysis demonstrated that degenerative cartilage degradation is seen to be larger for higher abnormalities. Moreover, numerical modeling of the new criterion allowed for the identification of OA phases based on the rate of cartilage wear measured for the various FE knee models.

Depth-Dependent Strain Model (1D) for Anisotropic Fibrils in Articular Cartilage.

The mechanical response of articular cartilage (AC) under compression is anisotropic and depth-dependent. AC is osmotically active, and its intrinsic osmotic swelling pressure is balanced by its collagen fibril network. This mechanism requires the collagen fibers to be under a state of tensile pre-strain. A simple mathematical model is used to explain the depth-dependent strain calculations observed in articular cartilage under 1D axial compression (perpendicular to the articular surface). The collagen fibers are under pre-strain, influenced by proteoglycan concentration (fixed charged density, FCD) and collagen stiffness against swelling stress. The stiffness is introduced in our model as an anisotropic modulus that varies with fibril orientation through tissue depth. The collagen fibers are stiffer to stretching parallel to their length than perpendicular to it; when combined with depth-varying FCD, the model successfully predicts how tissue strains decrease with depth during compression. In summary, this model highlights that the mechanical properties of cartilage depend not only on proteoglycan concentration but also on the intrinsic properties of the pre-strained collagen network. These properties are essential for the proper functioning of articular cartilage.

Sensitivity of simulated knee joint mechanics to selected human and bovine fibril-reinforced poroelastic material properties

Fibril-reinforced poroviscoelastic material models are considered state-of-the-art in modeling articular cartilage biomechanics. Yet, cartilage material parameters are often based on bovine tissue properties in computational knee joint models, although bovine properties are distinctly different from those of humans. Thus, we aimed to investigate how cartilage mechanical responses are affected in the knee joint model during walking when fibril-reinforced poroviscoelastic properties of cartilage are based on human data instead of bovine. We constructed a finite element knee joint model in which tibial and femoral cartilages were modeled as fibril-reinforced poroviscoelastic material using either human or bovine data. Joint loading was based on subject-specific gait data. The resulting mechanical responses of knee cartilage were compared between the knee joint models with human or bovine fibril-reinforced poroviscoelastic cartilage properties. Furthermore, we conducted a sensitivity analysis to determine which fibril-reinforced poroviscoelastic material parameters have the greatest impact on cartilage mechanical responses in the knee joint during walking. In general, bovine cartilage properties yielded greater maximum principal stresses and fluid pressures (both up to 30%) when compared to the human cartilage properties during the loading response in both femoral and tibial cartilage sites. Cartilage mechanical responses were very sensitive to the collagen fibril-related material parameter variations during walking while they were unresponsive to proteoglycan matrix or fluid flow-related material parameter variations. Taken together, human cartilage material properties should be accounted for when the goal is to compare absolute mechanical responses of knee joint cartilage as bovine material parameters lead to substantially different cartilage mechanical responses.

PIEZO1 is downregulated in glenohumeral chondrocytes in early cuff tear arthropathy following a massive rotator cuff tear in a mouse model.

Introduction: A massive rotator cuff tear (RCT) leads to glenohumeral joint destabilization and characteristic degenerative changes, termed cuff tear arthropathy (CTA). Understanding the response of articular cartilage to a massive RCT will elucidate opportunities to promote homeostasis following restoration of joint biomechanics with rotator cuff repair. Mechanically activated calcium-permeating channels, in part, modulate the response of distal femoral chondrocytes in the knee against injurious loading and inflammation. The objective of this study was to investigate PIEZO1-mediated mechanotransduction of glenohumeral articular chondrocytes in the altered biomechanical environment following RCT to ultimately identify potential therapeutic targets to attenuate cartilage degeneration after rotator cuff repair. Methods: First, we quantified mechanical susceptibility of chondrocytes in mouse humeral head cartilage ex vivo with treatments of specific chemical agonists targeting PIEZO1 and TRPV4 channels. Second, using a massive RCT mouse model, chondrocytes were assessed for mechano-vulnerability, PIEZO1 expression, and calcium signaling activity 14-week post-injury, an early stage of CTA. Results: In native humeral head chondrocytes, chemical activation of PIEZO1 (Yoda1) significantly increased chondrocyte mechanical susceptibility against impact loads, while TRPV4 activation (GSK101) significantly decreased impact-induced chondrocyte death. A massive RCT caused morphologic and histologic changes to the glenohumeral joint with decreased sphericity and characteristic bone bruising of the posterior superior quadrant of the humeral head. At early CTA, chondrocytes in RCT limbs exhibit a significantly decreased functional expression of PIEZO1 compared with uninjured or sham controls. Discussion: In contrast to the hypothesis, PIEZO1 expression and activity is not increased, but rather downregulated, after massive RCT at the early stage of cuff tear arthropathy. These results may be secondary to the decreased axial loading after glenohumeral joint decoupling in RCT limbs.