Irreversible Cartilage Damage Research Articles

Exosomes derived from MSC as drug system in osteoarthritis therapy.

Osteoarthritis (OA) is the most common degenerative disease of the joint with irreversible cartilage damage as the main pathological feature. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been found to have strong therapeutic potential. However, intraarticular MSCs injection therapy is limited by economic costs and ethics. Exosomes derived from MSC (MSC-Exos), as the important intercellular communication mode of MSCs, contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. With excellent editability and specificity, MSC-Exos function as a targeted delivery system for OA treatment, modulating immunity, inhibiting apoptosis, and promoting regeneration. This article reviews the mechanism of action of MSC-Exos in the treatment of osteoarthritis, the current research status of the preparation of MSC-Exos and its application of drug delivery in OA therapy.

MRI T2 mapping and quantitative ultrasound shear wave elastography in cartilage integrity assessment for juvenile idiopathic arthritis patients

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood that can lead to irreversible cartilage damage, with associated disability and decreased life quality. Shear wave elastography and quantitative MRI mapping can be used to identify early cartilage affection. PurposeTo evaluate diagnostic utility of distal femoral cartilage shear wave elastography and MRI T2 mapping in patients with symptomatic knee and investigate their potential clinical significance.Material and methodsTwenty patients with knee affection (study group) and 20 volunteers with the same demographic characteristics but without symptomatic knee pain (control group) were included in the study. A total of 80 knee joints of 40 individuals were evaluated. At the medial, intercondylar, and lateral condylar levels, distal femoral cartilage thickness was measured by B-mode ultrasonography and MRI, stiffness was assessed by shear wave elastography, and T2 relaxation time was measured by MRI.ResultsThe medial, intercondylar, and lateral cartilage thickness measurements were similar between the two groups and no statistically significant difference was observed while measured by US (P value 0.653,0.702,0.607) and MRI (P value 0.414, 0.4187, 0.3903). The shear wave velocity values in the study group were significantly higher than in the control group (P value 0.0202). There was a statistically significant difference between the average T2 relaxation time values for the distal femoral cartilage in the study and the control groups (P value 0.0027). SWE results were statistically significant in moderate and high disease activity while T2* revealed statistically significant p values in low as well as moderate and high disease activity; we found the best cutoff values for detection of cases using shear wave elastography velocity ratio (m/sec) about 4.445 with significant p value = 0.02, sensitivity 59.3% and specificity = 70.45%.ConclusionShear wave elastography and MRI T2 mapping are reliable, non-invasive, and acceptable methods for the assessment of pathologic cartilage. Better diagnostic information of hyaline cartilage can be obtained by adding up an extra sequence called T2 mapping to the routine MRI protocol of knee.

Mechanistic and therapeutic links between rheumatoid arthritis and diabetes mellitus.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and periarticular manifestations, RA is also a systematic disease associated with organ-specific extra-articular manifestation. Increasing evidence indicates that RA patients are susceptible to diabetes mellitus (DM), and RA aggravates metabolic disordered in DM, indicating the close association between RA and DM. Many factors involved in RA stimulate insulin resistance and DM development. These factors include proinflammatory cytokines (such as TNF-α, IL-6, IL-1β), RA autoantibodies (such as rheumatoid factor, cyclic citrullinated peptide antibodies), excess RA related adipokines (such as leptin, resistin, ANGPTL4), C-creative protein, and other protein (such as TXNDC5, NLRP3, RBP4). Furthermore, commonly used RA drugs, such as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), and glucocorticoids, provide potential benefits in improving insulin resistance and inhibiting DM development. This review discusses the mechanistic and therapeutic links between RA and DM, aiming to provide valuable information for the prevention and treatment of DM in RA patients.

Osteoarthritis-Related Inflammation Blocks TGF-β's Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region.

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.

A possible issue of articular cartilage degeneration in acute phase after anterior cruciate ligament reconstruction

A possible issue of articular cartilage degeneration in acute phase after anterior cruciate ligament reconstruction

Post-translational modification of the SMAD2/3 linker region: the missing link between osteoarthritis-related inflammation and disturbed transforming growth factor-β signaling

Purpose: Osteoarthritis (OA) is a degenerative joint disease characterized by inflammation and irreversible cartilage damage. The development of OA is associated with dysregulated transforming growth factor-β (TGF-β) signaling, e.g. with loss of SMAD2/3 signaling. Via intracellular activation of these transcription factors TGF-β inhibits chondrocyte hypertrophy and expression of cartilage degrading enzymes. Recently, it has been shown that post-translational modification of these SMAD proteins in their linker protein domain can dysregulate their function.

OA-related inflammation inhibits protective transforming growth factor-β signaling via post-translational modification of the SMAD2/3 linker region

Purpose: Osteoarthritis (OA) is a degenerative joint disease characterized by inflammation and irreversible cartilage damage. The development of OA is associated with dysregulated TGF-β signaling. Via intracellular activation of the transcription factors SMAD2 and SMAD3 this growth factor inhibits chondrocyte hypertrophy and expression of cartilage degrading enzymes. Recently, it has been shown that post-translational modification of these SMAD proteins in their linker protein domain can dysregulate TGF-β signaling.

Biomechanical Comparison of a New Dynamic Ankle Orthosis to a Standard Ankle-Foot Orthosis During Walking.

Patients who sustain irreversible cartilage damage or joint instability from ankle injuries are likely to develop ankle osteoarthritis (OA). A dynamic ankle orthosis (DAO) was recently designed with the intent to offload the foot and ankle using a distractive force, allowing more natural sagittal and frontal plane ankle motion during gait. To evaluate its efficacy, this study compared ankle joint kinematics and plantar pressures among the DAO, standard double upright ankle-foot orthosis (DUAFO), and a nonorthosis control (CON) condition in healthy adults during walking. Ten healthy subjects (26 ± 3.8 yr; 69.6 ± 12.7 kg; and 1.69 ± 0.07 m) walked on a treadmill at 1.4 m/s in three orthosis conditions: CON, DAO, and DUAFO. Ankle kinematics were assessed using a three-dimensional (3D) motion capture system and in-shoe plantar pressures were measured for seven areas of the foot. DAO reduced hallux peak plantar pressures (PPs) compared to CON and DUAFO. PPs under toes 2-5 were smaller in DAO than DUAFO, but greater in DUAFO compared to CON. Early stance peak plantarflexion (PF) angular velocity was smaller in DAO compared to CON and DUAFO. Eversion (EV) ROM was much smaller in DUAFO compared to CON and DAO. Early stance peak eversion angular velocity was smaller in DAO and much smaller in DUAFO compared to CON. This study demonstrates the capacity of the DAO to provide offloading during ambulation without greatly affecting kinematic parameters including frontal plane ankle motion compared to CON. Future work will assess the effectiveness of the DAO in a clinical osteoarthritic population.

Cartilage-on-cartilage cyclic loading induces mechanical and structural damage

Cartilage breaks down during mechanically-mediated osteoarthritis (OA). While previous research has begun to elucidate mechanical, structural and cellular damage in response to cyclic loading, gaps remain in our understanding of the link between cyclic cartilage loading and OA-like mechanical damage. Thus, the aim of this study was to quantify irreversible cartilage damage in response to cyclic loading. A novel in vitro model of damage through cartilage-on-cartilage cyclic loading was established. Cartilage was loaded at 1 Hz to two different doses (10,000 or 50,000 cycles) between -6.0 ± 0.2 MPa and -10.3 ± 0.2 MPa 1st Piola-Kirchhoff stress. After loading, mechanical damage (altered mechanical properties: elastic moduli and dissipated energy) and structural damage (surface damage and specimen thickness) were quantified. Linear and tangential moduli were determined by fitting the loading portion of the stress-strain curves. Dissipated energy was calculated from the area between loading and unloading stress-strain curves. Specimen thickness was measured both before and after loading. Surface damage was assessed by staining samples with India ink, then imaging the articular surface. Cyclic loading resulted in dose-dependent decreases in linear and tangential moduli, energy dissipation, thickness, and intact area. Collectively, these results show that cartilage damage can be initiated by mechanical loading alone in vitro, suggesting that cyclic loading can cause in vivo damage. This study demonstrated that with increased number of cycles, cartilage undergoes both tissue softening and structural damage. These findings are a first step towards characterizing the cartilage response to cyclic loading, which can ultimately provide important insight for delaying the initiation and slowing the progression of OA.

Therapiestrategie bei Gelenkinfektionen

Joint infections represent asevere complication that results in irreversible joint destruction when left untreated or treated inadequately. The reasons for joint infections include endogenous hematological and exogenous factors. In the patient cohort described here, the empyema was almost exclusively acquired through iatrogenic measures (e.g. arthroscopic operations, punctures and intra-articular infections) or as aresult of fractures close to the joint and penetrating injuries. Acute joint empyema is an orthopedic emergency, which must be immediately surgically treated because irreversible cartilage damage can rapidly occur due to the pathophysiological process. Acute joint empyema must be treated arthroscopically. Chronic empyema must be assumed when the clinical symptoms last for more than 7days. Chronic empyema should be treated by arthrotomy, synovectomy and removal of extraneous material including cruciate ligament replacement material.

Inflammatory Cytokines and Matrix Metalloproteinases in the Synovial Fluid After Intra-articular Ankle Fracture.

Posttraumatic osteoarthritis (PTOA) can occur after intra-articular fracture despite anatomic fracture reduction. It has been hypothesized that an early inflammatory response after intra-articular injury could lead to irreversible cartilage damage that progresses to PTOA. Therefore, in addition to meticulous fracture reduction, it would be ideal to prevent this initial inflammatory response but little is known about the composition of the synovial environment after intra-articular fracture. The purpose of this work was to characterize the inflammatory cytokine and matrix metalloproteinase (MMP) composition in the synovial fluid (SF) of patients with acute intra-articular ankle fractures. Twenty-one patients with an intra-articular ankle fracture were included in this study. All patients had a contralateral ankle joint that was pain free, had no radiographic evidence of arthritis, and no history of trauma. The uninjured ankle served as a matched control. SF was obtained from bilateral ankles at the time of surgery which occurred at a mean of 17 days post-fracture (range 8-40). The SF was analyzed for granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, CTXII, sGAG, and bilirubin/biliverdin (markers of hemearthrosis) using either multiplex assay or ELISA using commercially available kits. Mean concentrations of each factor were compared between SF from fractured and control ankles, and correlation analysis was done to determine potential relationships between levels of cytokines and time from fracture and age at fracture. Twelve of 18 measured factors including GM-CSF, IL-10, IL-1β, IL-6, IL-8, TNF-α, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, and bilirubin/biliverdin were found to be significantly higher in the fractured ankles. Mean concentrations of ECM degradation markers (sGAG and CTXII) were not found to be significatnly different between groups. These data indicate that after intra-articular ankle fracture the SF exhibits a largely pro-inflammatory and extra-cellular matrix degrading environment similar to that described in idiopathic osteoarthritis. IL-6, IL-8, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10 were significantly elevated and may play a role in the development of PTOA. In addition to anatomic fracture reduction, these data lend credence to reducing acute intra-articular inflammation through the development of antagonists to these pro-inflammatory and degrading mediators. Likewise, intra-articular lavage might reduce this inflammatory burden.

Gelenkinfekt – eine Entität für die spezielle septische Chirurgie

BackgroundJoint infections can cause severe complications that result in irreversible joint destruction when treated inadequately.PathogenesisReasons for joint infections consist of endogenous hematological and exogenous factors. Patients acquire empyema almost solely through iatrogenic measures (e.g. arthroscopic operations, punctures and intra-articular infections) or as a result of near joint fractures and penetrating injuries.DiagnosisTo make a correct diagnose, a joint puncture with a direct swab test is necessary in addition to laboratory examinations, x-ray and magnetic resonance imaging (MRI) examinations. The leucocyte count must be determined (threshold value 25,000/μl) as well as a gram stain to microscopically identify possible bacteria present.TherapyAcute joint infections are considered to be orthopedic emergencies necessitating immediate surgical treatment as irreversible cartilage damage can rapidly result due to the pathophysiological process. Acute joint empyema should be treated arthroscopically. Clinical symptoms lasting more than 7 days emanate in chronic empyema and should be treated by arthrotomy, synovialectomy and removal of extraneous material including a possible cruciate ligament replacement. Postoperatively, an immediate intensive physiotherapy is necessary, even under the use of pain catheters. The transfer to a centre for septic surgery is recommended.

Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis.

Osteoarthritis (OA) is a complex "whole joint" disease pursued by inflammatory mediators, rather than purely a process of "wear and tear". Besides cartilage degradation, synovitis, subchondral bone remodeling, degeneration of ligaments and menisci, and hypertrophy of the joint capsule take parts in the pathogenesis. Pain is the hallmark symptom of OA, but the extent to which structural pathology in OA contributes to the pain experience is still not well known. For the knee OA, intraarticular (IA) injection (corticosteroids, viscosupplements, blood-derived products) is preferred as the last nonoperative modality, if the other conservative treatment modalities are ineffective. IA corticosteroid injections provide short term reduction in OA pain and can be considered as an adjunct to core treatment for the relief of moderate to severe pain in people with OA. IA hyaluronic acid (HA) injections might have efficacy and might provide pain reduction in mild OA of knee up to 24 wk. But for HA injections, the cost-effectiveness is an important concern that patients must be informed about the efficacy of these preparations. Although more high-quality evidence is needed, recent studies indicate that IA platelet rich plasma injections are promising for relieving pain, improving knee function and quality of life, especially in younger patients, and in mild OA cases. The current literature and our experience indicate that IA injections are safe and have positive effects for patient satisfaction. But, there is no data that any of the IA injections will cause osteophytes to regress or cartilage and meniscus to regenerate in patients with substantial and irreversible bone and cartilage damage.

Blood-Induced Joint Damage: The Devastating Effects of Acute Joint Bleeds versus Micro-Bleeds.

Objective. Four days of blood exposure leads to irreversible cartilage damage in vitro. In contrast, intermittent intra-articular blood injections twice a week during 4 weeks (mimicking micro-bleeds) in a canine model resulted in transient damage only. In this study, it was evaluated whether acute joint bleeds are more harmful than micro-bleeds in a canine model of knee arthropathy. Design. Seven dogs received 4 sequential daily intra-articular blood injections twice in 2 weeks (mimicking 2 acute 4-day joint bleeds). Seven other dogs received the same blood load but in a total of 8 injections intermittently over the 4-week period with at least 1 day in between (mimicking micro-bleeds over the same timespan). Contralateral knees served as controls. Ten weeks after the last injection cartilage matrix turnover and synovial inflammation were evaluated. Results. Only after the acute joint bleeds the release of newly formed and total (resident) cartilage matrix glycosaminoglycans were increased (P = 0.04 and P = 0.01, respectively). Furthermore, in animals with the acute joint bleeds cartilage glycosaminoglycan content was decreased (P = 0.01) and not in animals with micro-bleeds. Mild synovial inflammation was observed in both groups (both P < 0.0001) but was not different between groups. Conclusions. In contrast to micro-bleeds, 2 acute joint bleeds lead to prolonged cartilage damage independent of the level of synovial inflammation. This model suggests that micro-bleeds are less devastating than acute joint bleeds with respect to joint damage, which might be of relevance to treatment of joint bleeds in clinical practice.

The application of optical coherence tomography in musculoskeletal disease.

Many musculoskeletal disorders (MDs) are associated with irreversible bone and cartilage damage; this is particularly true for osteoarthritis (OA). Therefore, a clinical need exists for modalities which can detect OA and other MDs at early stages. Optical coherence tomography (OCT) is an infrared-based imaging, currently FDA approved in cardiology and ophthalmology, which has a resolution greater than 10 microns and acquisition rate of 120 frames/second. It has shown feasibility for imaging early OA, identifying changes prior to cartilage thinning both in vitro and in vivo in patients and in OA animal models. In addition, OCT has shown an ability to identify early rheumatoid arthritis (RA) and guide tendon repair, but has the potential for an even greater impact. Clinical trials in OA are currently underway, as well as in several other MDs.

Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy

PurposeWith the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage.MethodsSubjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated.ResultsLevels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation.ConclusionThe temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.

NIR-fluorescence imaging points at a role for matrix-metalloproteinases in causing irreversible cartilage damage during collagen-induced arthritis

BackgroundDuring joint inflammation and destruction, a variety of proteases are upregulated, including different cathepsins and matrix-metalloproteinases (MMP). Enzyme activity and osteoblast activation can be quantitated in vivo by using activatable...

Reversibility of Immobilization-Induced Articular Cartilage Degeneration after Remobilization in Rat Knee Joints

Joint immobilization is commonly used for the treatment of joint injuries, but it causes articular cartilage degeneration. The purpose of this study was to clarify the reversibility of immobilization-induced articular cartilage degeneration using rat knee joints. Immobilization of rat knee joints induces atrophic changes in the non-contact area, loss of chondrocytes in the contact area, and hypertrophy of chondrocytes in the transitional area of the articular cartilage. The unilateral knee joints of adult male rats were rigidly immobilized at 150° of flexion with a plate and screws for 1, 2, and 4 weeks. After the experimental periods, the fixation devices were removed and the rats moved freely for 16 weeks. Sham-operated rats were used as a control. Sagittal sections at medial midcondylar regions of the knee were assessed with histological and histomorphometric methods. Mechanical properties were assessed by measuring the sound speed with scanning acoustic microscope. Reduction of cartilage proteoglycan in the non-contact area was almost reversible, but hypertrophy of chondrocytes in the transitional area and loss of chondrocytes in the contact area were irreversible even at 1-week immobilization-remobilization group. Sound speed of the articular cartilage in the contact area was not restored. These results indicate that atrophic changes through decreased mechanical stress in the non-contact area were reversible, but loss of chondrocytes and hypertrophy of chondrocytes in the contact and transitional areas through increased mechanical stress by rigid immobilization were irreversible after remobilization. Clinicians should be aware that even a short-term rigid immobilization could cause irreversible articular cartilage damage.

Femoroacetabular Impingement Surgical Techniques

Femoroacetabular impingement (FAI) is increasingly recognized as a disorder that can lead to progressive labral and chondral injury and early hip degeneration. The 2 primary structural abnormalities in the hip responsible for FAI are cam and pincer lesions. Recognition of these lesions through appropriate history, physical examination, and imaging is essential for early diagnosis and surgical correction before the progression of irreversible articular cartilage damage and joint degeneration. Arthroscopic surgical management of FAI involves resection of the pincer lesion in the central compartment with possible refixation of the labrum and/or decompression of the cam lesion in the peripheral compartment.

High-Field Magnetic Resonance Imaging Assessment of Articular Cartilage before and after Marathon Running

Background There is continuing controversy whether long-distance running results in irreversible articular cartilage damage. New quantitative magnetic resonance imaging (MRI) techniques used at 3.0 T have been developed including T1rho (T1ρ) and T2 relaxation time measurements that detect early cartilage proteoglycan and collagen breakdown. Hypothesis Marathon runners will demonstrate T1ρ and T2 changes in articular cartilage on MRI after a marathon, which are not seen in nonrunners. These changes are reversible. Study Design Cohort study; Level of evidence, 2. Methods Ten asymptomatic marathon runners had 3-T knee MRI scans 2 weeks before, within 48 hours after, and 10 to 12 weeks after running a marathon. The T1ρ and T2 MRI sequences in runners were compared with those of 10 age- and gender-matched controls who had MRI performed at baseline and 10 to 12 weeks. Results Runners did not demonstrate any gross morphologic MRI changes after running a marathon. Postmarathon studies, however, revealed significantly higher T2 and T1ρ values in all articular cartilage areas of the knee (P < .01) except the lateral compartment. The T2 values recovered to baseline except in the medial femoral condyle after 3 months. Average T1ρ values increased after the marathon from 37.0 to 38.9 (P < .001) and remained increased at 3 months. Conclusion Runners showed elevated T1ρ and T2 values after a marathon, suggesting biochemical changes in articular cartilage, T1ρ values remain elevated after 3 months of reduced activity. The patellofemoral joint and medial compartment of the knee show the highest signal changes, suggesting they are at higher risk for degeneration.