Structural Cartilage Damage Research Articles

Assessment of whole cartilage surface damage in an osteoarthritis rat model: The Cartilage Roughness Score (CRS) utilizing microcomputed tomography

ObjectiveThis study aims to establish an accurate and robust imaging biomarker for pre-clinical osteoarthritis (OA) research, focusing on early detection of cartilage surface degeneration. MethodUsing 50 male Wistar rats, this study aims to observe Collagenase Induced Osteoarthritis (CIOA) progression through microcomputed x-ray tomography (µCT), histopathological analysis, and gait analysis. A novel parameter, Cartilage Roughness Score (CRS), was developed for assessing cartilage structural damage from µCT data and was compared with histological OARSI Cartilage Degeneration Score (OARSI CDS). Additionally, as CRS maps the full surface, it was used to simulate the level of uncertainty in histological sampling. ResultsCRS and OARSI CDS have a linear relationship. CRS for healthy cartilage is 2.75 (95% CI: 1.14-4.36) and with every 1 unit increase in OARSI, CRS is expected to increase by 0.64 (95% CI: 0.35-0.92). Cartilage degeneration due to CIOA was evident in both histopathological scoring and CRS. However, only CRS was sensitive enough to show consistent damage progression from day 10 to day 60. Furthermore, our simulation for histological sampling suggested that up to 16 coronal slices with 200µm spacing would be needed to accurately represent the full extent of cartilage surface degeneration in a slice wise manner. Gait analysis showed changes solely at eight days post-collagenase injection, normalizing by day 60. ConclusionThe CRS analysis method emerges as a robust tool for cartilage surface damage assessment. This study demonstrates the potential of automatic 3D analysis over the traditional 2D histological approach when evaluating cartilage surface damage. Data statementMicro-computed tomography data is available via ida.fairdata.fi46 (https://doi.org/10.23729/f33d3ba8-01b8-47af-90dd-94b7c7861247)

A Review of Recent Innovations in Cartilage Regeneration Strategies for the Treatment of Primary Osteoarthritis of the Knee: Intra-articular Injections.

The pathology of primary osteoarthritis (OA) begins with structural cartilage damage, which initiates a self-propagating inflammatory pathway that further exacerbates cartilage deterioration. Current standard of care for knee primary OA involves treating the inflammatory symptoms to manage pain, which includes intra-articular (IA) injections of cortisone, an anti-inflammatory steroid, followed by a series of joint-cushioning hyaluronic acid gel injections. However, these injections do not delay the progression of primary OA. More focus on the underlying cellular pathology of OA has prompted researchers to develop treatments targeting the biochemical mechanisms of cartilage degradation. Researchers have yet to develop a United States Food and Drug Administration (FDA)-approved injection that has been demonstrated to significantly regenerate damaged articular cartilage. This paper reviews the current research on experimental injections aimed at achieving cellular restoration of the hyaline cartilage tissue of the knee joint. Narrative review. The authors conducted a narrative literature review examining studies on primary OA pathogenesis and a systematic review of non-FDA-approved IA injections for the treatment of primary OA of the knee, described as "disease-modifying osteoarthritis drugs" in phase 1, 2, and 3 clinical trials. New treatment approaches for primary OA investigate the potential of genetic therapies to restore native cartilage. It is clear that the most promising IA injections that could improve treatment of primary OA are bioengineered advanced-delivery steroid-hydrogel preparations, ex vivo expanded allogeneic stem cell injections, genetically engineered chondrocyte injections, recombinant fibroblast growth factor therapy, injections of selective proteinase inhibitors, senolytic therapy via injections, injectable antioxidant therapies, injections of Wnt pathway inhibitors, injections of nuclear factor-kappa β inhibitors, injections of modified human angiopoietin-like-3, various potential viral vector-based genetic therapy approaches, and RNA genetic technology administered via injections.

One session of 20 ​N cyclic compression induces chronic knee osteoarthritis in rats: A long-term study

ObjectiveMechanical stimulation is a risk factor for knee osteoarthritis. Non-surgical compression has been used to study the effects of mechanical stimulation in vivo. However, the long-term effects of low-force compression on knee joint had not been studied. Therefore, we sought to identify the long-term effects of low-force cyclic compression on the rat knee joint. DesignIn this study, we applied one session cyclic compression with a peak load of 20 ​N for 60 cycles to the rat knee joint in an approximately 140-degree flexion position (Wistar, male, 12 weeks old), followed by 1 year of observation (including data from 1 week, 2 weeks, 4 weeks, 8 weeks, 6 months, and 1 year after compression), and then performed a sub-regional analysis with hematoxylin-eosin, Safranin O and Fast Green, and MMP13 immunohistochemical staining. ResultsWe observed osteoarthritis-like cartilage damage, synovial inflammation, and high expression of MMP13 within 1 year after compression. However, these changes progressed slowly, with obvious matrix cracks that did not appear until 1 year after compression. In the regional analysis, we found that low-force compression caused a much slower development of injury at the compression contact site, and no significant structural cartilage damage was observed after 1 year of compression. In contrast, the non-contact site during compression at tibial cartilage in the same joint was the first to show significant structural damage. ConclusionThis study demonstrates that one session of 20 ​N cyclic compression induces a chronic osteoarthritis-like phenotype in the rat knee in the long term.

Mechanism of action of genicular artery embolization in a rabbit model of knee osteoarthritis.

To establish a rabbit osteoarthritis model for genicular artery embolization (GAE) experiments and to investigate the cellular mechanism of action of this novel procedure for interventional radiologists. Rabbit knee osteoarthritis was surgically modeled by anterior cruciate ligament transection and medial partial meniscectomy of the bilateral hindlimbs followed by 10 weeks of incubation. Rabbits exhibiting synovitis on magnetic resonance imaging were randomly divided into two groups: the bilateral GAE group and the control (sham procedure) group. Four weeks later, the rabbits' mobility (moving time, sec/10 min) and the histopathological features of each knee were assessed, and inter-group differences were evaluated using Student's t-test and ordinal/linear logistic models with generalized estimating equations. Osteoarthritis modeling and endovascular procedures were successful in 15 of 20 rabbits (8 and 7 in the GAE and control groups, respectively). There was no significant difference in moving times between the two groups (p = .958). The degree of structural cartilage damage was similar in both groups (p = .780). However, the synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) scores were significantly lower in the GAE group than in the control group. The CD3+ cell density (p = .018) and CD3 + cell-infiltrated area (p = .019) were also significantly lower in the GAE group than in the control group. GAE can limit inflammatory processes in the synovium of osteoarthritis-affected knees. Surgical transection of the anterior cruciate ligament and medial partial meniscectomy of rabbit knees provides a useful animal model for research of genicular artery embolization. Osteoarthritic knees treated by genicular artery embolization showed milder synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) than the untreated knees. Osteoarthritic knees treated by genicular artery embolization presented lower CD3+ cell density (p = .018) and CD3+ cell-infiltrated area (p = .019) in the synovium than the untreated knees.

Localization of Nerve Growth Factor Expression to Structurally Damaged Cartilaginous Tissues in Human Lumbar Facet Joint Osteoarthritis.

PurposeNerve Growth Factor (NGF) is a pivotal mediator of chronic pain and plays a role in bone remodelling. Through its high affinity receptor TrkA, NGF induces substance P (SP) as key downstream mediator of pain and local inflammation. Here we analysed NGF, TrkA and SP tissue distribution in facet joint osteoarthritis (FJOA), a major cause of chronic low back pain.MethodsFJOA specimens (n=19) were harvested from patients undergoing intervertebral fusion surgery. Radiologic grading of FJOA and spinal stenosis, followed by immunohistochemistry for NGF, TrkA and SP on consecutive tissue sections, was performed in ten specimens. Explant cultures (n=9) were used to assess secretion of NGF, IL-6, and SP by FJOA osteochondral tissues under basal and inflammatory conditions.ResultsNGF was predominantly expressed in damaged cartilaginous tissues (80%), occasionally in bone marrow (20%), but not in osteochondral vascular channels. NGF area fraction in cartilage was not associated with the extent of proteoglycan loss or radiologic FJOA severity. Consecutive sections showed that NGF and SP expression was localized at structurally damaged cartilage, in absence of TrkA expression. SP and TrkA were expressed in subchondral bone marrow in both presence and absence of NGF. Low level NGF, but not SP secretion, was detected in four out of eighteen FJOA explants under both basal or inflammatory conditions (n=2 each).ConclusionNGF is associated with SP expression and structural cartilage damage in osteoarthritic facet joints, but not with radiologic disease severity. NGF tissue distribution in FJOA differs from predominant subchondral bone expression reported for knee OA.

Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis

BackgroundThe objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA.DesignDunkin-Hartley guinea pigs develop mild primary OA pathology by 5 months of age that progresses to moderate OA by 8 months of age. At 5 months, guinea pigs served as young control (n = 3) or were fed either a control diet (n = 8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14 ppm, n = 8), or Rap with the AMPK-activator metformin (Rap+Met, 1000 ppm, n = 8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting.ResultsRap- and Rap+Met-treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap- and Rap+Met-treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress after Rap treatment was related to worsened OA.ConclusionsThis is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not appear to protect against primary OA during the prevailing hyperglycemia.

Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50±SD: 19±2nM and <23±1nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20μM and 10μM, respectively). In DMM mice, GLPG1972/S201086 (30-120mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

Investigation of the relationship between trochlear morphology and medial patellar cartilage defect using magnetic resonance imaging

The aim of this study was to evaluate trochlear morphology in patients with medial patellar cartilage defects via magnetic resonance imaging (MRI). Three hundred patients who were diagnosed with grade 2, 3 and 4 medial patellar cartilage defect using MRI according to the International Cartilage Repair Society Classification System and 100 control subjects were evaluated. Trochlear morphology was evaluated based on lateral trochlear inclination (LTI), medial trochlear inclination (MTI), sulcus angle( SA), femoral lateral and medial condyle symmetry, trochlear facet asymmetry, and trochlear width on the axial MR images. The mean SA was significantly higher in the medial patellar cartilage defect group compared to the control group (p<.05). The LTI and MTI of the cartilage defect group were significantly lower than those of the control group (p<.05). With the decreasing LTI and MTI, there was an increase in medial patellar cartilage loss. LTI (r=-0.46) and MTI (r=-0.53) were moderately correlated with SA. There was no significant differences in femoral lateral and medial condyle symmetry, trochlear facet asymmetry, and trochlear width between groups with and without medial patellar cartilge defect (p ˃ .05). A flattened medial trochlea is a risk factor for cartilage structural damage of the medial patellofemoral joint, and it plays a role in the development of a defect in the medial patellar cartilage. The medial patellar cartilage defect is associated with the flattened lateral trochlea.

Preclinical Study of the Efficacy and Safety of Chondroitin Sulfate

Chondroitin sulfate is used for osteoarthritis combination therapy. It should be taken into account that the structure and properties of polysaccharides included in chondroitin sulfate, as well as the raw materials used for its production, have a significant effect on its absorption, bioavailability, and, as a consequence, on the safety and efficacy of orally administered products.The aim of the study was to assess toxic properties, local irritant effect, immunotoxicity, basic pharmacokinetic parameters, and therapeutic efficacy of the new Chondroitin sulfate product (produced by Federal State Unitary Enterprise “Moscow Endocrine Plant”, Russia) as compared to Structum (produced by “Pierre Fabre Medicament Production”, France).Materials and methods: White Giant rabbits were used in the experiments. Toxicity, immunotoxicity and local irritation effects of the products were assessed following daily oral administration at the dose of 168 mg/kg (about 6 Maximum Recommended Therapeutic Doses) to male and female rabbits for 28 days. The follow-up period was 14 days. The pharmacokinetic study included blood sampling on days 1‒2 of the experiment, complete blood count and blood chemistry tests were performed on days 28 and 43. After killing the animals, pathomorphological and histological examinations were performed on their organs and tissues. Therapeutic efficacy was studied in an osteoarthritis model made by cruciate ligament transaction in rabbits. The animals received therapy at doses of 16.8 mg/kg, 33.6 mg/kg, and 67.2 mg/kg for 56 days starting from day 8 after the pathology induction.Results: the medicines had no toxic, local irritant, or immunotoxic effect. The NOAEL was established at 168 mg/kg. The study demonstrated the comparability of the pharmacokinetic profiles of the studied products following single oral administration. The maximum concentration of the active ingredient (Cmax = 79 ± 6 μg/mL—Chondroitin sulfate; Cmax = 71 ± 4 μg/mL— Structum) in blood plasma was observed within 3–4 hours after administration. A decrease in the severity of cartilage structural damage was observed for the doses of 33.6 mg/kg and 67.2 mg/kg. The results of quantitative determination of sulfated glycosaminoglicans in the proteoglycans of the cartilage articular surface in the animals with osteoarthritis demonstrated an increase in the level of sulfated glycosaminoglicans in the groups treated with the maximum doses of the studied products, as compared to the other groups.Conclusions: the obtained data confirm that the test product has a favourable safety profile, and therapeutic (chondroprotective) effect. All the tested properties of Chondroitin sulfate were comparable to those of Structum.

Correlation of T2* relaxation times of the retropatellar cartilage with tibial tuberosity\u2013trochlea groove distance in professional soccer players

The tibial tuberosity–trochlear groove (TT–TG) distance is a radiographic measurement that is used to quantify malalignment of the patellofemoral joint (PFJ) in cross-sectional imaging. There is an ongoing debate about the impact of the TT–TG-distance on lateral patellar instability and the initiating of cartilage degeneration. In this prospective study, the association of T2* relaxation times and TT–TG distances in professional soccer players was analyzed. 36 knees of 18 professional soccer players (age: 21 ± 2.8 years) were evaluated. Participants underwent knee MRI at 3 T. For qualitative image analysis, fat-saturated 2D PD-weighted Fast Spin Echo (FSE) and T1-weighted FSE sequences were used. For quantitative analysis, T2* measurements in 3D data acquisitions were performed. In a qualitative analysis there was no structural cartilage damage and no abnormalities of the patellar and trochlea shape. The highest T2* values (26.7 ± 5.9 ms) were observed in the central compartment of the patella. The mean TT–TG distance was 10 ± 4 mm (range 3–20 mm). There was no significant correlation between TT–TG distance and T2* relaxation times in all three compartments of the retropatellar cartilage. Our study shows that so long as patellar and trochlear morphology is normal, TT–TG distance alone does not affect the tissue structure of the retropatellar cartilage in professional soccer players.

Differential patterns of pathology in and interaction between joint tissues in long-term osteoarthritis with different initiating causes: phenotype matters

To determine if osteoarthritis (OA) progression and joint tissue-pathology associations link specific animal models to different human OA phenotypes. Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logistic-regression. Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r>0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r>0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r>0.4), SCB sclerosis (r>0.26), osteophyte size (r>0.3), and maturity (r>0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r=0.56), osteophyte maturity (r=0.49), size (r=0.45), and SCB sclerosis (r=0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r=0.40) and osteophyte size (r=0.37); and synovitis with cartilage structural damage (r=0.18). No tissue-pathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR=2.0) and proteoglycan loss (OR=2.4) in DMM; and synovitis (OR=1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR=1.4) and inversely with osteophyte size (OR=0.21) in AIA only. This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology.

T1\u03c1-mapping for assessing knee joint cartilage in children with juvenile idiopathic arthritis \u2014 feasibility and repeatability

BackgroundOngoing arthritis in children with juvenile idiopathic arthritis (JIA) can result in cartilage damage.ObjectiveTo study the feasibility and repeatability of T1ρ for assessing knee cartilage in JIA and also to describe T1ρ values and study correlation between T1ρ and conventional MRI scores for disease activity.Materials and methodsThirteen children with JIA or suspected JIA underwent 3-tesla (T) knee MRI that included conventional sequences and a T1ρ sequence. Segmentation of knee cartilage was carried out on T1ρ images. We used intraclass correlation coefficient to study the repeatability of segmentation in a subset of five children. We used the juvenile arthritis MRI scoring system to discriminate inflamed from non-inflamed knees. The Mann-Whitney U and Spearman correlation compared T1ρ between children with and without arthritis on MRI and correlated T1ρ with the juvenile arthritis MRI score.ResultsAll children successfully completed the MRI examination. No images were excluded because of poor quality. Repeatability of T1ρ measurement had an intraclass correlation coefficient (ICC) of 0.99 (P<0.001). We observed no structural cartilage damage and found no differences in T1ρ between children with (n=7) and without (n=6) inflamed knees (37.8 ms vs. 31.7 ms, P=0.20). However, we observed a moderate correlation between T1ρ values and the juvenile arthritis MRI synovitis score (r=0.59, P=0.04).ConclusionThis pilot study suggests that T1ρ is a feasible and repeatable quantitative imaging technique in children. T1ρ values were associated with the juvenile arthritis MRI synovitis score.

Quantitative articular cartilage sub-surface defect assessment using optical coherence tomography: An in-vitro study

Assessment of structural cartilage damage is of high scientific and clinical interest. Optical Coherence Tomography (OCT) is a light-based cross-sectional imaging modality that allows the real-time assessment of articular cartilage at near-histological resolution. Algorithm routines for the detection, parameterization and quantification of sub-surface defects as assessed by OCT were implemented and validated in this study.Standard defects of 0.9mm, 1.1mm and 1.3mm diameter were created in the sub-surface regions of macroscopically intact human articular cartilage samples (n=60 defects of variable sizes in n=20 samples). Subsequently, samples were scanned by 3D OCT and defect size, height, width and distance to the surface were determined based on the algorithm and related to manual measurements. Histology served as the standard-of-reference. Statistical analysis included one-way ANOVA’s and Tukey’s post-hoc test.All defects were correctly identified by the algorithm, while five structural tissue inhomogeneities were erroneously marked as defects (sensitivity 100%, specificity: 92.3%). Inter-modality analysis revealed no significant differences in terms of defect area, height or width within the different defect sizes, while the distance to the surface was significantly different.The comprehensive algorithm-based characterization of cartilage defects is consistent and reliable and allows their more objective evaluation. Given further research in this field, OCT and OCT-based quantitative measures may become clinically useful in the arthroscopic detection and evaluation of sub-surface cartilage defects.

Bioluminescence and second harmonic generation imaging reveal dynamic changes in the inflammatory and collagen landscape in early osteoarthritis

Osteoarthritis (OA) is a leading cause of chronic disability whose mechanism of pathogenesis is largely elusive. Local inflammation is thought to play a key role in OA progression, especially in injury-associated OA. While multiple inflammatory cytokines are detected, the timing and extent of overall inflammatory activities in early OA and the manner by which joint inflammation correlates with cartilage structural damage are still unclear. We induced OA via destabilization of the medial meniscus (DMM) in NFκB luciferase reporter mice, whose bioluminescent signal reflects the activity of NFκB, a central mediator of inflammation. Bioluminescence imaging data showed that DMM and sham control joints had a similar surge of inflammation at 1-week post-surgery, but the DMM joint exhibited a delay in resolution of inflammation in subsequent weeks. A similar trend was observed with synovitis, which we found to be mainly driven by synovial cell density and inflammatory infiltration rather than synovial lining thickness. Interestingly, an association between synovitis and collagen structural damage was observed in early OA. Using Second Harmonic Generation (SHG) imaging, we analyzed collagen fiber organization in articular cartilage. Zonal differences in collagen fiber thickness and organization were observed as soon as OA initiated after DMM surgery, and persisted over time. Even at 1-week post-surgery, the DMM joint showed a decrease in collagen fiber thickness in the deep zone and an increase in collagen fiber disorganization in the superficial zone. Since we were able detect and quantify collagen structural changes very early in OA development by SHG imaging, we concluded that SHG imaging is a highly sensitive tool to evaluate pathological changes in OA. In summary, this study uncovered a dynamic profile of inflammation and joint cartilage damage during OA initiation and development, providing novel insights into OA pathology.

Defining the factors that alter OA risk following ACL injury using pre-clinical animal models

Purpose: Osteoarthritis (OA) is a common long-term outcome of anterior cruciate ligament (ACL) injuries, but still only ∼50% of ACL deficient knees develop OA. Concomitant meniscal or chondral damage substantially increases OA risk, however factors affecting OA development in isolated ACL tears are less defined. There is evidence to suggest that the impact at the time of ACL injury may be an important risk factor in addition to altered joint mechanics. The aim of this study was to investigate changes in joint mechanics, pain behaviours and OA pathogenesis in models of isolated ACL injury comparing minimal impact trauma (surgical transection) with compression induced ligament failure (mechanical rupture). Methods: Ten-week-old, male C57BL/6 mice were randomised into 4 groups: 1) uninjured, 2) sham surgery, 3) surgical ACL transection (ACLT), or 4) mechanical ACL rupture (mACLR). Outcomes were measured at 1, 2, 4 and 8 weeks post-injury. Ex vivo knee mechanics (range of motion and joint stiffness) were measured using an anterior-posterior (AP) laxity tester (n = 6/group). Pain behaviour was assessed using von Frey filaments (mechanical allodynia) or an incapacitance tester (static weight-bearing) and included pre-injury tests (n = 6/group). OA severity in the medial and lateral tibiofemoral compartments was scored histologically for: proteoglycan loss, cartilage structural damage, osteophyte development, subchondral bone sclerosis and synovitis (n = 7/group). Results: ACL injury significantly altered the mechanics of the knee whilst sham surgery did not differ from uninjured joints. AP range of motion increased equally (3-fold) following ACLT and mACLR (P < 0.02), with no improvement up to 8 weeks post-injury. Anterior joint stiffness increased over time in controls. ACLT stiffness was significantly lower than sham at 1 and 2 weeks post-injury (P < 0.02) with some recovery at 4 weeks, whilst mACLR remained largely unchanged but significantly less than uninjured at 4 and 8 weeks post-injury (P < 0.01). Significant mechanical allodynia was equally evident at all time points following sham surgery, ACLT and mACLR (P < 0.001 vs pre-injury). In contrast, weight-bearing was only reduced in ACL injured limbs (1–8 weeks post-injury, P < 0.01 vs pre-injury both ACLT and mACLR). OA pathology was found in both the medial and lateral compartments, but was substantially worse in the former. Differences between the two ACL injury models were also more evident medially. The development and progression of medial cartilage pathology was slower following ACLT compared to mACLR: proteoglycan loss and cartilage damage were not significantly increased until 8 weeks post-ACLT (P < 0.005) whilst mACLR induced significant changes by week 2 (P < 0.001). Similarly, significant osteophyte formation was not evident until 8 weeks post-ACLT (P < 0.005) but was present 1 week after mACLR (P < 0.005). Subchondral bone sclerosis was elevated following mACLR but was not significantly different from ACLT or controls. Synovitis was greatest following ACLT at 1 week post-injury (P < 0.005) but was no different between ACLT, mACLR and sham surgery from 2–4 weeks. At 8 weeks, sham surgery synovitis had returned to uninjured levels whilst ACLT and mACLR remained slightly elevated (P < 0.005). Conclusions: These results show that loss of ACL integrity, irrespective of the mechanism of injury, causes severely altered joint mechanics and increased pain responses. Despite these functional and symptomatic similarities, pathological progression of disease was vastly different between the two models. ACL transection results in a slowly progressive OA whilst compressive rupture induces rapid onset and progression. These findings indicate that pain and anterior–posterior joint mechanics are not predictive of OA severity but the acute trauma itself can significantly influence the outcome of disease. Defining ways to determine compressive loading experienced at the time of ACL injury, could improve prediction of OA risk and patient management.

Structural cartilage damage attracts circulating rheumatoid arthritis synovial fibroblasts into affected joints

BackgroundRheumatoid arthritis synovial fibroblasts (RASFs) are known to travel via the bloodstream from sites of cartilage destruction to new locations where they reinitiate the destructive processes at distant articular cartilage surfaces. In this study, we examined the role of interleukin (IL)-1-induced cartilage changes and their chemotactic effect on RASF transmigratory capacity.MethodsTo investigate synovial fibroblast (SF) transmigration through endothelial layers, we used a modified Boyden chamber with an endothelioma cell layer (bEnd.5) as a barrier and IL-1-treated murine cartilage explants as a chemotactic stimulus for SFs from human tumor necrosis factor–transgenic (hTNFtg) mice. We injected recombinant IL-1 or collagenase into knee joints of wild-type mice, followed by tail vein injection of fluorescence-labeled hTNFtg SFs. The distribution and intensity of transmigrating hTNFtg SFs were measured by fluorescence reflectance imaging with X-ray coregistration. Toluidine blue staining was performed to evaluate the amount of cartilage destruction.ResultsHistomorphometric analyses and in vivo imaging revealed a high degree of cartilage proteoglycan loss after intra-articular IL-1 and collagenase injection, accompanied by an enhanced in vivo extravasation of hTNFtg SFs into the respective knee joints, suggesting that structural cartilage damage contributes significantly to the attraction of hTNFtg SFs into these joints. In vitro results showed that degraded cartilage was directly responsible for the enhanced transmigratory capacity because stimulation with IL-1-treated cartilage, but not with IL-1 or cartilage alone, was required to increase hTNFtg SF migration.ConclusionsThe present data indicate that structural cartilage damage facilitates the migration of arthritic SF into affected joints. The prevention of early inflammatory cartilage damage may therefore help prevent the progression of rheumatoid arthritis and its spread to previously unaffected joints.

Association between trochlear morphology and chondromalacia patella: an MRI study

This study aimed to compare trochlear morphology seen in magnetic resonance imaging between patients with chondromalacia patella and age-matched control patients without cartilage lesion. Trochlear morphology was evaluated using the lateral trochlear inclination, medial trochlear inclination, sulcus angle and trochlear angle on the axial magnetic resonance images. Consequently, an association between abnormal trochlear morphology and chondromalacia patella was identified in women. In particular, women with flattened lateral trochlea are at an increased risk of patellar cartilage structural damage.

The relationship of autophagy defects to cartilage damage during joint aging in a mouse model.

Aging is a main risk factor for osteo arthritis (OA), the most prevalent musculoskeletal disorder. Defects in autophagy, an essential cellular homeostasis mechanism, have recently been observed in OA articular cartilage. The objectives of this study were to establish the constitutive level of autophagy activation in normal cartilage and to monitor the temporal relationship between changes in autophagy and aging-related degradation of cartilage in a mouse model. In GFP-LC3-transgenic mice, green fluorescent protein (GFP)-light chain 3 (LC3) is ubiquitously expressed, and the accumulation of GFP puncta, representing autophagosomes, was quantified by confocal microscopy as a measure of autophagy activation. Expression of the autophagy proteins autophagy-related protein 5 (ATG-5) and microtubule-associated protein 1 light chain 3 (LC3) was analyzed by immunohistochemistry. Cartilage cellularity, apoptotic cell death, and cartilage structural damage and changes in synovium and bone were examined by histology and immunohistochemistry. Basal autophagy activation was detected in liver and knee articular cartilage from young (6-month-old) mice, with higher levels in cartilage than in liver in the same animals. In 28-month-old mice, there was a statistically significant reduction in the total number of autophagic vesicles per cell (P < 0.01) and in the total area of vesicles per cell (P < 0.01) in the articular cartilage as compared to that from young 6-month-old mice. With increasing age, the expression of ATG-5 and LC3 decreased, and this was followed by a reduction in cartilage cellularity and an increase in the apoptosis marker poly(ADP-ribose) polymerase p85. Cartilage structural damage progressed in an age-dependent manner subsequent to the autophagy changes. Autophagy is constitutively activated in normal cartilage. This is compromised with aging and precedes cartilage cell death and structural damage.

Lack of sclerostin promotes osteoarthritis by activating canonical and non-canonical WNT pathways

Lack of sclerostin promotes osteoarthritis by activating canonical and non-canonical WNT pathways

FRI0320 Radiographic features, better than clinical features, represent actual joint degeneration and inflammation: Considerations for total knee replacement surgery

BackgroundClinically, osteoarthritis (OA) is characterized by joint pain, tenderness, limitation of movement, crepitus, occasional effusion, and local inflammation. Pain, joint deformation, and stiffness of the joint capsule may lead to...