Progression Of Cartilage Degeneration Research Articles

EVALUATION OF CHONDROPROTECTIVE EFFICACY OF TRIAMCINOLONE IN OSTEOARTHRITIS INDUCED RAT MODEL

ABSTRACT
 BACKGROUND AND OBJECTIVE:
 Osteoarthritis is one of the most common joint diseases afflicting human, characterized by progressive degeneration of articular cartilage in which chondrocytes fails to adequately repair. Objective of this study is to evaluate the chondroprotection offered by triamcinolone in osteoarthritis induced rat model
 METHODOLOGY:
 This Laboratory based experimental study was conducted in Department of Pharmacology, Army Medical College, Rawalpindi, in collaboration with National Institute of health, Islamabad from April-June2019. Osteoarthritis was induced by surgical removal of medial meniscus and anterior cruciate ligament resection in right knee joint of Sixteen (16) anesthetized rats of Sprague Dawley breed. They were divided in two (02) groups with eight (08) rats in each group. Group I was disease control in which 0.2 ml Intra articular saline was administered for three weeks. While group II was treatment group that was treated by 70 µl intra articular triamcinolone once weekly for three weeks. After that gait pattern of rats was scored. Animals were euthanized with over dosage of inhaled chloroform and sample of proximal tibia was taken for histopathological analysis.RESULTS:
 Mean gait score of control group and treatment group was 3.25±.707 and 2.25±.463 with a p value of .028 that is statistically significant. While mean histopathological modified Mankin score of control and treatment group was 11.5±1.195 and 8.5±1.195 respectively with a significant P-value of <0.01.
 CONCLUSION:
 Intra articular administration of triamcinolone in Osteoarthritis induced rats resulted in improvement in gait pattern and histopathology.
 Keywords: Chondroprotective efficacy, Osteoarthritis, Triamcinolone.

Xanthohumol Attenuated Inflammation and ECM Degradation by Mediating HO-1/C/EBPβ Pathway in Osteoarthritis Chondrocytes

Osteoarthritis (OA) is the most frequent and disabling disease in developed countries. The progressive degeneration of articular cartilage characterized as thinner and erosive. Inflammation is well-known to be involved in OA development. However, there are no effective therapeutic strategies to cure it. Xanthohumol (XH) is a natural prenylflavonoid isolated from hops and beer. The protective activity of XH against OA chondrocytes inflammation and ECM degradation is unclear. In this article, we found that XH significantly inhibited inflammatory responses, attenuated catabolic enzymes expression, and ameliorated ECM degradation, as showed by decreased production of NO, PGE2, TNFα, and IL-6, decreased expression of MMP-3/-13 and ADAMTS-4/-5, and increased expression of collagen-II and aggrecan. In addition, XH activated HO-1 signaling and attenuated IL-1β-induced C/EBPβ. XH promoted the interaction between HO-1 and C/EBPβ, inhibiting the nuclear translocation of C/EBPβ. HO-1 knockdown could abrogate the protective effects of XH in IL-1β-treated chondrocytes. Collectively, XH attenuated inflammatory responses and ECM degradation by mediating HO-1 and C/EBPβ signaling pathways in osteoarthritis chondrocytes.

Changes of type II collagenase biomarkers on IL-1β-induced rat articular chondrocytes.

Osteoarthritis (OA) is characterized by progressive degeneration of cartilage, formation of cartilage at the cartilage edge, and remodeling of the subchondral bone. Pro-inflammatory cytokines [e.g., interleukin (IL)-1β] that induce inflammation and promote chondrocyte damage induce OA. Currently, the diagnosis of OA is commonly based on imaging examinations (e.g., X-ray) and evaluations of clinical symptoms; however, biomarkers that can effectively diagnose OA are currently not available. By studying the mechanism underlying OA cartilage injury and changes in the concentrations of the biomarkers procollagen type II carboxy-terminal propeptide (PIICP), collagen type-II C-telopeptide fragments (CTX-II), and type II collagen cleavage neoepitope (C2C) during pathogenesis, the present study established a theoretical basis for the evaluation and early diagnosis of OA. In an experiment, 10 ng/ml IL-1β was used to the treat chondrocyte-induced OA models in vitro for 0, 12, 24 and 48 h. Western blotting was used to detect the expression levels of matrix metalloproteinase (MMP)-3, MMP-13, and inducible nitric oxide synthase (iNOS) protein at each time-point. The concentrations of CTX-II, C2C, and PIICP in the cell culture supernatant were detected by ELISA kit. A biochemical kit was used to detect changes of nitric oxide (NO) in the cell culture supernatant. In addition, chondrocytes were treated with 10 ng/ml IL-1β for 0, 30, 60 and 90 min and the translocation and phosphorylation of the NF-κB pathway were investigated by western blotting. Following IL-1β stimulation, the NF-κB pathway was activated to increase the expression levels of MMPs and iNOS synthesis downstream of the pathway, resulting in an increased degradation of type II collagen (Col II). To sum up, pro-inflammatory IL-1β induced an OA chondrocyte model. During the development of OA, the expression of MMPs and NO increased and Col II was degraded.

The NC1 fragment of type X collagen measured in serum as a potential biomarker of osteoarthritis

Purpose: The chondrocytes taking a terminal differentiation route of hypertrophy, invasion of blood vessels from the subchondral bone, apoptosis, and calcification of cartilage has been observed in experimental models of OA and human osteoarthritis (OA). Hypertrophy-like changes in chondrocytes are recently believed to play a role in the initiation and progression of cartilage degeneration. Type X collagen, a well-known marker of hypertrophy chondrocytes, plays a role in facilitating and regulating endochondral ossification of cartilage.

Acteoside Counteracts Interleukin-1β-Induced Catabolic Processes through the Modulation of Mitogen-Activated Protein Kinases and the NFκB Cellular Signaling Pathway.

Osteoarthritis (OA) is the most common degenerative joint disease with chronic joint pain caused by progressive degeneration of articular cartilage at synovial joints. Acteoside, a caffeoylphenylethanoid glycoside, has various biological activities such as antimicrobial, anti-inflammatory, anticancer, antioxidative, cytoprotective, and neuroprotective effect. Further, oral administration of acteoside at high dosage does not cause genotoxicity. Therefore, the aim of present study is to verify the anticatabolic effects of acteoside against osteoarthritis and its anticatabolic signaling pathway. Acteoside did not decrease the viabilities of mouse fibroblast L929 cells used as normal cells and primary rat chondrocytes. Acteoside counteracted the IL-1β-induced proteoglycan loss in the chondrocytes and articular cartilage through suppressing the expression and activation of cartilage-degrading enzyme such as matrix metalloproteinase- (MMP-) 13, MMP-1, and MMP-3. Furthermore, acteoside suppressed the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2 in the primary rat chondrocytes treated with IL-1β. Subsequently, the expression of proinflammatory cytokines was decreased by acteoside in the primary rat chondrocytes treated with IL-1β. Moreover, acteoside suppressed not only the phosphorylation of mitogen-activated protein kinases in primary rat chondrocytes treated with IL-1β but also the translocation of NFκB from the cytosol to the nucleus through suppression of its phosphorylation. Oral administration of 5 and 10 mg/kg acteoside attenuated the progressive degeneration of articular cartilage in the osteoarthritic mouse model generated by destabilization of the medial meniscus. Our findings indicate that acteoside is a promising potential anticatabolic agent or supplement to attenuate or prevent progressive degeneration of articular cartilage.

Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)-approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.

Osteoarthritic Subchondral Bone Release Exosomes That Promote Cartilage Degeneration.

Altered subchondral bone and articular cartilage interactions have been implicated in the pathogenesis of osteoarthritis (OA); however, the mechanisms remain unknown. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication. Herein, we investigated if OA subchondral bone derived exosomes alter transcriptional and bioenergetic signatures of chondrocytes. Exosomes were isolated and purified from osteoblasts of nonsclerotic or sclerotic zones of human OA subchondral bone and their role on the articular cartilage chondrocytes was evaluated by measuring the extent of extracellular matrix production, cellular bioenergetics, and the expression of chondrocyte activity associated marker genes. Exosomal microRNAs were analyzed using RNA sequencing and validated by quantitative real-time PCR and loss-of-function. In coculture studies, chondrocytes internalized OA sclerotic subchondral bone osteoblast derived exosomes and triggered catabolic gene expression and reduced chondrocyte-specific marker expression a phenomenon that is often observed in OA cartilage. RNA sequencing and miRNA profiling have identified miR-210-5p, which is highly enriched in OA sclerotic subchondral bone osteoblast exosomes, triggered the catabolic gene expression in articular cartilage chondrocytes. Importantly, we demonstrate that miR-210-5p suppresses the oxygen consumption rate of chondrocytes, altering their bioenergetic state that is often observed in OA conditions. These effects were markedly inhibited by the addition of a miR-210-5p inhibitor. Our study indicates that exosomes released by OA sclerotic subchondral bone osteoblasts plays a critical role in progression of cartilage degeneration and might be a potential target for therapeutic intervention in OA.

Ergosterol limits osteoarthritis development and progression through activation of Nrf2 signaling.

Osteoarthritis (OA) is a common joint disorder characterized by progressive articular cartilage degeneration and destruction and results in gradual disability among middle-aged and elderly patients. Our previous study demonstrated that depletion of nuclear factor erythroid 2-related factor 2 (Nrf2) exacerbated cartilage erosion in an OA model and that activation of the Nrf2 pathway could counter this process. As a downstream target of Nrf2, heme oxygenase (HO) degrades heme to free iron, biliverdin and carbon monoxide (CO), which protects against oxidative stress. Ergosterol (ER), which is extracted from fungi, is a newly discovered Nrf2 activator and displayed efficacy against myocardial injury. The present study aimed to investigate the potential protective effects of ER against cartilage damage during OA. Primary mouse chondrocytes were treated with ER for in vitro assays. Furthermore, mice that underwent destabilization of the medial meniscus surgery were orally administered with ER. Western blotting suggested that ER increased protein expression of Nrf2 and HO-1 in primary chondrocytes and articular cartilage from knee joints. Cartilage damage in knee joints was significantly reduced by ER treatment. Western blotting and PCR analysis confirmed that ER could also suppress the expression of MMP-9 and MMP-13 in vivo and in vitro. The present findings suggested that ER effectively alleviated cartilage degradation and that activation of the Nrf2-heme oxygenase 1 pathway may play a role in ER-mediated cartilage protection against OA.

Functional, Magnetic Resonance Imaging, and Second-Look Arthroscopic Outcomes After Pullout Repair for Avulsion Tears of the Posterior Lateral Meniscus Root

Background: Little data exist in the literature regarding second-look arthroscopic outcomes after pullout repair for avulsion tears of the posterior lateral meniscus root. Purpose: To (1) assess the functional, magnetic resonance imaging (MRI), and second-look arthroscopic outcomes after pullout repair for avulsion tears of the posterior lateral meniscus root; (2) determine which demographic and clinical factors influenced healing of the repaired posterior lateral meniscus root; and (3) compare outcomes between different meniscal healing status groups. Study Design: Case series; Level of evidence, 4. Methods: A total of 31 patients underwent pullout repair for avulsion tears of the posterior lateral meniscus root and had a minimum 2-year follow-up. Functional outcomes were assessed using patient-reported scores (Lysholm, Tegner, and International Knee Documentation Committee [IKDC] scores). Lateral meniscal extrusion, cartilage degeneration of the lateral compartment, and healing of the repaired posterior lateral meniscus root were assessed via MRI. The healing status was also assessed using second-look arthroscopic surgery, and the patients were divided into different healing status groups. Results: The postoperative patient-reported scores improved significantly compared with the preoperative values (P = .001). Lateral meniscal extrusion was reduced significantly from 3.37 ± 0.82 mm preoperatively to 0.63 ± 0.80 mm at final follow-up (P = .001). The grade of cartilage degeneration of the lateral compartment progressed from 0.69 ± 0.67 preoperatively to 0.95 ± 0.83 at final follow-up (P = .213). MRI scans showed complete healing in 28 patients (90.3%) and partial healing in 3 patients (9.7%). Second-look arthroscopic surgery showed stable healing in 18 of 23 patients (78.3%) and lax healing in 5 of 23 patients (21.7%). Patients with stable healing had significantly higher Lysholm and IKDC scores, more reduction of meniscal extrusion, and less progression of cartilage degeneration than did patients with lax healing (P < .05). Concomitant anterior cruciate ligament reconstruction was found to significantly positively influence healing of the repaired posterior lateral meniscus root (P = .047). Conclusion: Pullout repair for avulsion tears of the posterior lateral meniscus root yielded significantly improved patient-reported scores, reduced meniscal extrusion, and a satisfactory healing rate at final follow-up. Patients with stable healing had significantly better functional and MRI outcomes than did patients with lax healing.

Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity

Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity in its clinical presentation, and is associated with autoantibodies directed against modified self-epitopes. Although many models already exist for RA for preclinical research, many current model systems of arthritis have limited predictive value because they are either based on animals of phylogenetically distant origin or suffer from overly simplified in vitro culture conditions. These limitations pose considerable challenges for preclinical research and therefore clinical translation. Thus, a sophisticated experimental human-based in vitro approach mimicking RA is essential to (i) investigate key mechanisms in the pathogenesis of human RA, (ii) identify targets for new therapeutic approaches, (iii) test these approaches, (iv) facilitate the clinical transferability of results, and (v) reduce the use of laboratory animals. Here, we summarize the most commonly used in vitro models of RA and discuss their experimental feasibility and physiological proximity to the pathophysiology of human RA to highlight new human-based avenues in RA research to increase our knowledge on human pathophysiology and develop effective targeted therapies.

Preoperative flexion contracture is a predisposing factor for cartilage degeneration at the patellofemoral joint after open wedge high tibial osteotomy

PurposeThe purpose of the study was to determine the effect of cartilage degeneration at the patellofemoral joint on clinical outcomes after open wedge high tibial osteotomy and to investigate the predisposing factors for progressive patellofemoral cartilage degeneration.MethodsSeventy-two knees were evaluated on second-look arthroscopy in patients who opted for plate and screw removal at an average of 20.1 months after osteotomy. Cartilage degeneration at the patellofemoral joint was evaluated using the International Cartilage Repair Society grading system, with cases divided into progression and nonprogression groups. Radiographic parameters of the patellofemoral anatomy, knee range of motion, and clinical outcomes were evaluated from the preoperative baseline to the final follow up, on average 50 months after osteotomy. A contracture > 5° was considered a flexion contracture.ResultsCartilage degeneration progressed in 31 knees, and preoperative knee flexion contracture was significantly associated with progressive degeneration (P < 0.01). The Lysholm and Kujala scores were significantly lower in the progression group (87.9 and 85.3, respectively) than in the nonprogression group (91.6 and 93.6, respectively) (P < 0.05). The odds ratio of the flexion contracture resulting in progression of patellofemoral cartilage degeneration was 4.63 (95% confidence interval, 1.77–12.1). No association was detected between progressive degeneration and age, sex, body mass index, Kellgren-Lawrence grade, or radiographic parameters.ConclusionsFlexion contracture may be associated with progression of cartilage degeneration at the patellofemoral joint and may negatively affect the clinical outcomes after open wedge, high tibial osteotomy.

Mouse CD105+ Stem/Progenitor Cells on Amino-Group-Functionalized Biosilica-Hydrogel Scaffolds for Cartilage Regeneration: An In Vitro Study

Temporomandibular disorders (TMDs) are widely spread within the population, and a subgroup has progressive degenerative changes with progressive cartilage degeneration and subchondral bone remodeling. Ten to 17% of patients have TMJ osteoarthritis (OA).1,2 Mesenchymal stem/progenitor cells (MSPCs) are critical for tissue regeneration. Moreover, CD105 antigen identifies early MSPCs with increased chondrogenic differentiation ability. The aim of this study was to evaluate a mouse temporomandibular joint (TMJ) derived CD105+ MSPC subgroup (mCoSPC) on functionalized biosilica incorporating hydrogel scaffolds, under chondrogenic stimulus, on fibrocartilage composition for cartilage formation.

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis.

Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.

Natural history of new horizontal meniscal tears in individuals at risk for and with mild to moderate osteoarthritis: data from osteoarthritis initiative.

To study the natural history of new horizontal meniscal tears and their association with progression of cartilage degeneration in individuals at risk for or with mild to moderate knee osteoarthritis over 4years. Individuals who developed a new meniscal tear in the right knee over 2years were selected from the Osteoarthritis Initiative 3T MRI studies. Knee structural changes were analyzed at the time of tear appearance (baseline), and after 4years using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Meniscal tears were classified as either horizontal tears or non-horizontal tears. Individuals without a meniscal tear were 1:3 frequency matched according to BMI, gender, race, and age and served as the control group. Linear regression analysis was used to compare cross-sectional and longitudinal changes in cartilage WORMS scores. Forty-one subjects developed horizontal tears, including one indiviudal who developed a tear in both menisci, and 34 developed non-horizonal tears. We found that (29/41 (70.7%)) of horizontal and (20/34 (58.8%)) of non-horizonatal tears were stable during follow-up (p = 0.281). Although knees with an incident tear had higher than controls WORMS MAX total knee scores at baseline (coef. = 0.47, p = 0.044, 95% CI = 0.01 to 0.93), there were no significant differences between the horizontal subgroup and knees without tears in overall cartilage scores at baseline and in progression over 4years of follow-up. New horizontal meniscal tears tended to be stable over 4years and presented no significant differences in progression of cartilage degeneration when compared with knees without tears. • Most of horizonal meniscal tears were stable over 4years. • There were no statistically significant differences in overall progression of cartilage degenerative changes between knees with horizonal meniscal tears and control knees without tears • Horizontal tears most often occurred at the posterior horn of the medial meniscus and at the body of the lateral meniscus.

Adipose tissue-derived mesenchymal stem cells and chitosan/poly (vinyl alcohol) nanofibrous scaffolds for cartilage tissue engineering

Osteoarthritis (OA) has been defined as a chronic inflammatory joint disease characterized by progressive articular cartilage degeneration. Recently growing interest in regenerative medicine, using cell therapy and tissue engineering, where cellular components in combination with engineered scaffolds and bioactive materials were used to induce functional tissue regeneration. In the present study, nanofibrous scaffold based on chitosan (CS)/poly (vinyl alcohol) (PVA) were used to develop biologically functionalized biomaterial to mimic the extracellular matrix, allowing the human adipose tissue derived mesenchymal stem cells (ADSCs) to proliferate and differentiate to chondrogenic cells. The morphology of the nanofibrous mat was examined using field emission scanning electron microscope (FE/SEM). The characteristic functional groups and the nature of the chemical bonds between atoms were evaluated using Fourier transform infrared spectroscopy (FTIR) spectrum. Characterization of the seeded cells was morphologically evaluated by scanning electron microscopy and by flow cytometry for the expression of the stem cell surface markers. The differentiation potential was verified after chondrogenic induction by analyzing the expression of chondrogenic marker genes using real-time (RT PCR). Current study suggest significant potential for the use of ADSCs with the nanofibrous scaffolds in improving the osteoarthritis pathology.

Myricitrin regulates proliferation, apoptosis and inflammation of chondrocytes treated with IL-1β

Osteoarthritis (OA) is a clinical disease which seriously affects the quality of life of sufferers. Although the pathogenesis of OA has not been fully unraveled, it is may be due to increased levels of pro-inflammatory cytokines, activation of inflammation-related signaling pathways, and degradation of extracellular matrix. Osteoarthritis is characterized by chronic joint pain, swelling, stiffness, limited movement or joint deformity, all of which seriously affect the quality of life and health of the affected individuals. Myroside (Myr) is a polyphenolic hydroxyflavone glycoside extracted from the fruits, bark and leaves of myroside and other natural plants. It has many pharmacological properties, especially anti-inflammatory effects. In the present study, primary chondrocytes of IL-1β rats were used to simulate pathological environment of chondrocytes in OA, and to explore the effect of Myr on chondrocytes. It was found that Myr improved the viability and proliferation of chondrocytes, and also inhibited apoptosis in these cells. Moreover, Myr reduced the expressions of inflammatory factors, and inhibited inflammatory reactions in chondrocytes. These findings provide good experimental basis for the clinical application of Myr in the prevention and treatment of progressive degeneration of cartilage in OA.

Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental temporomandibular joint osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by progressive cartilage degeneration, abnormal bone remodeling, and chronic pain. In this study, we aimed to investigate effective therapies to reverse or suppress TMJOA progression. To this end, we performed intravenous administration of serum free conditioned media from human exfoliated deciduous teeth stem cells (SHED-CM) into a mechanical-stress induced murine TMJOA model. SHED-CM administration markedly suppressed temporal muscle inflammation, and improved bone integrity and surface smoothness of the destroyed condylar cartilage. Moreover, SHED-CM treatment decreased the number of IL-1β, iNOS, and MMP-13 expressing chondrocytes, whereas it specifically increased PCNA-positive cells in the multipotent polymorphic cell layer. Notably, the numbers of TdT-mediated dUTP nick end labeling (TUNEL)-positive apoptotic chondrocytes in the SHED-CM treated condyles were significantly lower than in those treated with DMEM, whereas the proteoglycan positive area was restored to a level similar to that of the sham treated group, demonstrating that SHED-CM treatment regenerated the mechanical-stress injured condylar cartilage and subchondral bone. Secretome analysis revealed that SHED-CM contained multiple therapeutic factors that act in osteochondral regeneration. Our data demonstrated that SHED-CM treatment promoted the regeneration and repair of mechanical-stress induced mouse TMJOA. Our observations suggest that SHED-CM has potential to be a potent tissue-regenerating therapeutic agent for patients with severe TMJOA.

The innate immune pattern-recognition receptor CD14 influences osteoclastogenesis and the persistence of synovial leukocyte infiltration after joint injury in mice

Purpose: CD14 is a macrophage co-receptor that facilitates Toll-like receptor signaling. Deficiency of CD14 protects mice from subchondral bone pathology and progression of cartilage degeneration in a murine model of post-traumatic OA. CD14 is highly expressed by myeloid cells including monocytes, macrophages, and osteoclast precursors and can influence activity of these cell types. Binding of TLR ligands to the CD14/TLR complex activates inflammatory signaling cascades and promotes chronic inflammation, and many TLR ligands have been implicated in OA pathogenesis.

Impact of controlling abnormal joint movement on the effectiveness of subsequent exercise intervention in mouse model of early knee osteoarthritis

Purpose: Moderate mechanical stress is necessary for preserving the cartilage. Recent evidence from animal models of surgically induced OA indicates that the progression of cartilage degeneration can be delayed by moderate exercise. On the other hand, joint instability induces excessive mechanical stress contributes to OA onset and progression. The anterior cruciate ligament transection (ACL-T) model, which is a commonly used animal model of surgically induced OA. In contrast, the controlled abnormal joint movement (CAJM) model, proposed by (Murata et al. 2017) and (Onitsuka et al. 2018) involves ACL-T followed by another surgical procedure to re-stabilize the joint and reduce joint instability. In the CAJM model, the expression of inflammatory factors and cartilage matrix degrading factors is suppressed, joint instability is reduced, and progression to OA is slower. We hypothesized that exercise intervention is more effective at preventing the degeneration of articular cartilage in knee OA if joint instability is controlled. Methods: This study used 28 adults (12-week-old) ICR male mice. The mice were divided into 4 experimental groups: ACL-T without exercise intervention, CAJM without exercise intervention, ACL-T with exercise intervention (ACL-T/Ex), and CAJM with exercise intervention (CAJM/Ex). For mice assigned to CAJM groups, a 25-gauge needle was used to create bone tunnels in the anterior portion of the proximal tibia and in the posterior portion of the femoral condyle in order to decrease the anterior translation of the tibia onto the femur. Subsequently, 4-0 nylon thread was passed through the bone tunnels to compensate for ACL function and help control the anterior translation of the tibia. To assess knee joint instability, the anterior drawer test was performed using a constant force spring (0.05 kgf; Sanko Spring Co., Ltd., Fukuoka, Japan) and a soft X-ray device (M-60; Softex Co., Ltd., Kanagawa, Japan). Mice allocated to the exercise groups (ACL-T/Ex and CAJM/Ex) were exercised on a rodent treadmill, were exercised on the treadmill at a constant speed of 18 m/min for 30 min/d, 3 d/wk, for 4 weeks. Thin sections (7 μm) were cut in the sagittal plane, stained with safranin-O/fast green, and subjected to histology evaluation to estimate the degree of cartilage damage. Two independent observers (T Kano and KO) per- formed OARSI scoring on a scale of 8 stages (0, 0.5, 1-6), and the average value was retained. To evaluate the expression of IL-1βand MMP-13, we performed immuno- histochemical staining using the avidin-biotinylated enzyme complex method. For analysis, we calculated the ratio between the number of IL-1β- or MMP-13-positive cells and the number of chondrocytes in an articular cartilage area of 10000 μm2 (100 μm × 100 μm). Results: Joint instability was quantified using X-ray radiography with the anterior drawer test (Fig. 1A).Compared with the ACL-T and ACL-T/Ex groups, the CAJM and CAJM/Ex groups had significantly lower anterior displacement of the tibia (p<0.05) (Fig. 1B).In the ACL-T/Ex group, marked surface fibrillation and reduction in cartilage thickness were noted in the posterior part of the articular cartilage, together with a significantly higher OARSI score than that noted for the other 3 groups (p<0.001) (Fig. 2). With regard to inflammation, IL-1β-positive cells were confirmed from the cartilage surface layer to the deep layer in the ACL-T, CAJM, and ACL-T/Ex groups but not in the CAJM/Ex group (Fig. 3A). The percentage of IL-1β- positive cells in the anterior part of the cartilage was significantly higher in the ACL-T and ACL-T/Ex groups than in the CAJM/Ex group, the percentage of IL-1β-positive cells in the posterior part of the cartilage was significantly higher for the ACL-T and ACL-T/Ex groups than for the CAJM/Ex group (p<0.05) (Fig. 3B). Similarly, MMP-13-positive cells were confirmed in the ACL-T and ACL-T/Ex groups, compared with very weak MMP-13 expression in the CAJM and CAJM/Ex groups (Fig. 3A). However, while no significant difference among the four groups was noted in terms of the percentage of MMP-13-positive cells in the anterior part of the cartilage, the percentage of MMP-13-positive cells in the posterior part of the cartilage was significantly higher for the ACL-T/Ex group than for the CAJM/Ex group (p=0.02) (Fig. 3C). Conclusions: Previous studies reported that exercise alone could delay the progress of OA. However, our present Results indicate that the internal environment of the joint strongly modulates the effect of exercise, sometimes completely canceling the benefit. In other words, when prescribing exercise, we need to consider the internal environment of the knee joint.In the clinical setting, these findings may trans- late in the need to consider an intervention to correct abnormal joint movement before prescribing physical exercise in the treatment of OA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Biological regeneration in a compartmentalized early stage of osteoarthritis: 12-month results of a randomized trial in sheep

Purpose: Progressive degeneration of articular cartilage, resulting from a local cartilage defect, is a key feature of osteoarthritis (OA), the most common form of joint disease in the western world today. Middle-aged people who participate in sporting activities have expectations for recovery and therefore are unsuitable for joint replacement surgery, as high activity demands may lead to early failure. Therefore, the goal of this study was to adjust the conventional operation technique and to compare three different methods for biological repair in a large animal model with long-term follow-up.