scholarly journals Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2

2020 ◽  
Vol 13 (7) ◽  
pp. dmm044719 ◽  
Author(s):  
Craig M. Keenan ◽  
Lorenzo Ramos-Mucci ◽  
Ioannis Kanakis ◽  
Peter I. Milner ◽  
Andrew Leask ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Knee Joints ◽  
Matricellular Protein ◽  
Micro Computed Tomography ◽  
Non Invasive ◽  
Post Surgery ◽  
Osteoarthritis Research Society ◽  
Post Traumatic

ABSTRACTCCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. Ccn2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). Ccn2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-computed tomography and processed for histology. Sections were stained with Toluidine Blue and scored using the Osteoarthritis Research Society International (OARSI) grading system. In the non-invasive model, cartilage lesions were present in the lateral femur, but no significant differences were observed between wild-type (WT) and Ccn2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments, but no significant differences were observed between WT and Ccn2 KO mice at 2, 4 and 8 weeks post-surgery. We conclude that Ccn2 deletion in chondrocytes does not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a crucial factor in protecting cartilage from the degeneration associated with PTOA.This article has an associated First Person interview with the first author of the paper.

scholarly journals Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of CCN2

2020 ◽  
Author(s):  
Craig M Keenan ◽  
Lorenzo Ramos-Mucci ◽  
Ioannis Kanakis ◽  
Peter I Milner ◽  
Andrew Leask ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Knee Joints ◽  
Matricellular Protein ◽  
Non Invasive ◽  
Post Surgery ◽  
Surgical Model ◽  
Summary Statement ◽  
Post Traumatic

AbstractCCN2 is a matricellular protein involved in several critical biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. CCN2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development, however its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). CCN2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-CT, and processed for histology. Sections were stained with toluidine blue and scored using the OARSI grading system. In the non-invasive model cartilage lesions were present in the lateral femur but no significant differences were observed between wildtype (WT) and CCN2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments but no significant differences were observed between WT and CCN2 KO mice at 2, 4, and 8 weeks post-surgery. We conclude that CCN2 deletion in chondrocytes did not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a critical player in protecting cartilage from the degeneration associated with PTOA.Summary StatementPost-natal deletion of CCN2 in chondrocytes does not affect the development of post-traumatic osteoarthritis in mice.

scholarly journals Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1462
Author(s):  
Aimy Sebastian ◽  
Jillian L. McCool ◽  
Nicholas R. Hum ◽  
Deepa K. Murugesh ◽  
Stephen P. Wilson ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Single Cell ◽  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Cell Types ◽  
Knee Joints ◽  
Molecular Changes ◽  
Post Traumatic ◽  
Joint Trauma ◽  
Functional Profiles

Articular cartilage is a connective tissue lining the surfaces of synovial joints. When the cartilage severely wears down, it leads to osteoarthritis (OA), a debilitating disease that affects millions of people globally. The articular cartilage is composed of a dense extracellular matrix (ECM) with a sparse distribution of chondrocytes with varying morphology and potentially different functions. Elucidating the molecular and functional profiles of various chondrocyte subtypes and understanding the interplay between these chondrocyte subtypes and other cell types in the joint will greatly expand our understanding of joint biology and OA pathology. Although recent advances in high-throughput OMICS technologies have enabled molecular-level characterization of tissues and organs at an unprecedented resolution, thorough molecular profiling of articular chondrocytes has not yet been undertaken, which may be in part due to the technical difficulties in isolating chondrocytes from dense cartilage ECM. In this study, we profiled articular cartilage from healthy and injured mouse knee joints at a single-cell resolution and identified nine chondrocyte subtypes with distinct molecular profiles and injury-induced early molecular changes in these chondrocytes. We also compared mouse chondrocyte subpopulations to human chondrocytes and evaluated the extent of molecular similarity between mice and humans. This work expands our view of chondrocyte heterogeneity and rapid molecular changes in chondrocyte populations in response to joint trauma and highlights potential mechanisms that trigger cartilage degeneration.

Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway

Rheumatology ◽  
2021 ◽  
Author(s):  
Liangliang Liu ◽  
Chang Zhao ◽  
Haiyan Zhang ◽  
Yuheng Lu ◽  
Bingsheng Luo ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Medial Meniscus ◽  
Articular Chondrocytes ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Osteoarthritis Progression ◽  
Osteoarthritis Research Society ◽  
Tgf Β1

Abstract Objectives This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in osteoarthritis (OA) pathology. Methods Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated β-galactosidase (SA-βGal) staining, γH2AX, p21, and p16INK4a were analyzed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-β1/Smad2 signaling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. Results Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-β1/Smad2 signaling in chondrocytes. Conclusions Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-β1/Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p/asporin/Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.

scholarly journals Comparison of properties determined using electromechanical assessment (Arthro-BST™) with macroscopic and histological properties in symptomatic human articular cartilage of the hip

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Taku Ukai ◽  
Masato Sato ◽  
Shiho Wasai ◽  
Takumi Takahashi ◽  
Haruka Omura ◽  
...  
Keyword(s):  
Histological Grade ◽  
Cartilage Damage ◽  
Hip Osteoarthritis ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Cartilage Tissue ◽  
Human Articular Cartilage ◽  
Mankin Score ◽  
Osteoarthritis Research Society ◽  
Noninvasive Assessment

Abstract Background Cartilage degeneration is assessed using various methods. Although macroscopic evaluation can directly measure cartilage degeneration, it cannot accurately assess cartilage properties. Histological examination is one of the most accurate methods for evaluating cartilage degeneration. However, it is invasive and requires collection of cartilage tissue. In contrast, the Arthro-BST™ probe can assess cartilage properties noninvasively. This study aimed to evaluate the effectiveness of the Arthro-BST in assessing cartilage degeneration by comparing macroscopic (International Cartilage Repair Society [ICRS] classification) and histological evaluations (modified Mankin score and Osteoarthritis Research Society International [OARSI] histological grade). Methods Fourteen femoral heads were excised from 13 patients during surgery to treat hip osteoarthritis or femoral fracture. The ICRS score was used for macroscopic evaluation of cartilage degeneration. The Arthro-BST was applied at sites matching the areas of cartilage damage. The sites assessed using the ICRS classification and Arthro-BST were evaluated histologically (modified Mankin score and OARSI histological grade), and these were compared with the Arthro-BST results. Results The ICRS classification identified significant differences between grades 1 and 3 (p < 0.01), between grades 1 and 4 (p < 0.01), between grades 2 and 3 (p < 0.01), and between grades 2 and 4 (p < 0.01). Significant correlations were observed between the Arthro-BST results and the ICRS score, modified Mankin score (structure, cellularity, matrix staining, total score), and OARSI histological grade. Conclusions In the assessment of hip osteoarthritis, the Arthro-BST results correlated with those of macroscopic and histological evaluations. The Arthro-BST is useful for assessing hip osteoarthritis and may be helpful for noninvasive assessment of cartilage degeneration.

scholarly journals Meloxicam ameliorates the cartilage and subchondral bone deterioration in monoiodoacetate-induced rat osteoarthritis

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3185 ◽  
Author(s):  
Előd Nagy ◽  
Enikő Vajda ◽  
Camil Vari ◽  
Sándor Sipka ◽  
Ana-Maria Fárr ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Low Dose ◽  
Late Phase ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Bone Lesions ◽  
High Dose ◽  
Low Grade ◽  
Male Wistar Rats ◽  
Osteoarthritis Research Society

ObjectiveThis study aimed to quantify the cartilage- and subchondral bone-related effects of low-dose and high-dose meloxicam treatment in the late phase of mono-iodoacetate-induced osteoarthritis of the stifle.MethodsThirty-four male Wistar rats received intra-articular injection of mono-iodoacetate to trigger osteoarthritis; 10 control animals (Grp Co) received saline. The mono-iodoacetate-injected rats were assigned to three groups and treated from week 4 to the end of week 7 with placebo (Grp P,n = 11), low-dose (GrpM Lo, 0.2 mg/kg,n = 12) or high-dose (GrpM Hi, 1 mg/kg,n = 11) meloxicam. After a period of 4 additional weeks (end of week 11) the animals were sacrificed, and the stifle joints were examined histologically and immunohistochemically for cyclooxygenase 2, in conformity with recommendations of the Osteoarthritis Research Society International. Serum cytokines IL-6, TNFα and IL-10 were measured at the end of weeks 3, 7, and 11.ResultsCompared with saline-treated controls, animals treated with mono-iodoacetate developed various degrees of osteoarthritis. The cartilage degeneration score and the total cartilage degeneration width were significantly lower in both the low-dose (p = 0.012 andp = 0.014) and high-dose (p = 0.003 andp = 0.006) meloxicam-treated groups than in the placebo group. In the subchondral bone, only high-dose meloxicam exerted a significant protective effect (p = 0.011). Low-grade Cox-2 expression observed in placebo-treated animals was abolished in both meloxicam groups. Increase with borderline significance of TNFα in GrpP from week 3 to week 7 (p = 0.049) and reduction of IL-6 in GrpM Lo from week 3 to week 11 (p = 0.044) were observed.ConclusionIn this rat model of osteoarthritis, both low-dose and high-dose meloxicam had a chondroprotective effect, and the high dose also protected against subchondral bone lesions. The results suggest a superior protection of the high-dose meloxicam arresting the low-grade inflammatory pathway accompanied by chronic cartilage deterioration.

scholarly journals Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis

2021 ◽  
Author(s):  
Kaamini M Dhanabalan ◽  
Ameya A Dravid ◽  
Smriti Agarwal ◽  
Ramanath K Sharath ◽  
Ashok K Padmanabhan ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Symptomatic Relief ◽  
Cartilage Damage ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Cartilage Degeneration ◽  
Current Standard ◽  
Disease Modifying Drugs ◽  
Post Traumatic ◽  
Sulphated Glycosaminoglycans

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.

scholarly journals Metformin limits osteoarthritis development and progression through activation of AMPK signalling

2020 ◽  
Vol 79 (5) ◽  
pp. 635-645 ◽  
Author(s):  
Jun Li ◽  
Bin Zhang ◽  
Wei-Xiao Liu ◽  
Ke Lu ◽  
Haobo Pan ◽  
...  
Keyword(s):  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Research Society ◽  
Cartilage Tissue ◽  
Protective Effects ◽  
Joint Injury ◽  
Synovial Hyperplasia ◽  
Medial Meniscectomy ◽  
Osteoarthritis Research Society ◽  
Amp Activated Protein Kinase

ObjectivesIn this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression.MethodsDestabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by μCT and MRI in non-human primates.ResultsMetformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates.ConclusionsThe present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.

scholarly journals Impact of Controlling Abnormal Joint Movement on the Effectiveness of Subsequent Exercise Intervention in Mouse Models of Early Knee Osteoarthritis

Cartilage ◽  
2019 ◽  
pp. 194760351988500
Author(s):  
Yuichiro Oka ◽  
Kenji Murata ◽  
Takuma Kano ◽  
Kaichi Ozone ◽  
Kohei Arakawa ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Exercise Intervention ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Joint Movement ◽  
Knee Oa ◽  
Osteoarthritis Research Society ◽  
Anterior Cruciate ◽  
Safranin O

Objective Moderate mechanical stress is necessary for preserving the cartilage. The clinician empirically understands that prescribing only exercise will progress osteoarthritis (OA) for knee OA patients with abnormal joint movement. When prescribing exercise for OA, we hypothesized that degeneration of articular cartilage could be further prevented by combining interventions with the viewpoint of normalizing joint movement. Design Twelve-week-old ICR mice underwent anterior cruciate ligament transection (ACL-T) surgery in their right knee and divided into 4 groups: ACL-T, controlled abnormal joint movement (CAJM), ACL-T with exercise (ACL-T/Ex), CAJM with exercise (CAJM/Ex). Animals in the walking group were subjected to treadmill exercise 6 weeks after surgery, which included walking for 18 m/min, 30 min/d, 3 d/wk for 4 weeks. Joint instability was measured by anterior drawer test, and safranin-O staining and immunohistochemical staining were performed. Results OARSI (Osteoarthritis Research Society International) score of ACL-T/Ex group showed highest among 4 groups ( P < 0.001). And CAJM/Ex group was lower than ACL-T/Ex group. Positive cell ratio of IL-1β and MMP-13 in CAJM/Ex group was lower than ACL-T/Ex group ( P < 0.05). Conclusions We found that the state of the intra-articular environment can greatly influence the effect of exercise on cartilage degeneration, even if exercise is performed under the same conditions. In the CAJM/Ex group where joint movement was normalized, abnormal mechanical stress such as shear force and compression force accompanying ACL cutting was alleviated. These findings may highlight the need to consider an intervention to correct abnormal joint movement before prescribing physical exercise in the treatment of OA.

Comparison of Properties Determined Using Electromechanical Assessment (Arthro-BSTTM) With Macroscopic and Histological Properties in Symptomatic Human Articular Cartilage of the Hip

2021 ◽  
Author(s):  
Taku Ukai ◽  
Masato Sato ◽  
Shiho Wasai ◽  
Takumi Takahashi ◽  
Haruka Omura ◽  
...  
Keyword(s):  
Histological Grade ◽  
Cartilage Damage ◽  
Hip Osteoarthritis ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Cartilage Tissue ◽  
Histological Evaluation ◽  
Human Articular Cartilage ◽  
Mankin Score ◽  
Osteoarthritis Research Society

Abstract Background: Cartilage degeneration is assessed using various methods. Although macroscopic evaluation can measure cartilage degeneration directly, it cannot accurately assess cartilage properties. Histological examination is one of the most accurate methods for evaluating cartilage degeneration. However, it is invasive and requires collection of cartilage tissue. By contrast, the Arthro-BSTTM probe can assess cartilage properties noninvasively. This study aimed to evaluate the effectiveness of the Arthro-BST for assessing cartilage degeneration by comparing macroscopic evaluation (International Cartilage Repair Society [ICRS] classification) and histological evaluation (modified Mankin score and Osteoarthritis Research Society International [OARSI] histological grade).Methods: Fourteen femoral heads were excised from 13 patients during surgery to treat hip osteoarthritis or femoral fracture. The ICRS score was used for macroscopic evaluation of cartilage degeneration. The Arthro-BST was applied at sites matching the areas of cartilage damage. The sites assessed using the ICRS classification and Arthro-BST were evaluated histologically (modified Mankin score and OARSI histological grade), and these were compared with the Arthro-BST results.Results: ICRS classification identified significant differences between grades 1 and 3 (p < 0.01), grades 1 and 4 (p < 0.01), grades 2 and 3 (p < 0.01), and grades 2 and 4 (p < 0.01). Significant correlations were observed between the Arthro-BST results and the ICRS score, modified Mankin score (structure, cellularity, matrix staining, total score), and OARSI histological grade.Conclusions: In the assessment of hip osteoarthritis, Arthro-BST results correlated with those of macroscopic and histological evaluation. The Arthro-BST is useful for assessing hip osteoarthritis and may be helpful for the noninvasive assessment of cartilage degeneration.

scholarly journals Disuse Atrophy of Articular Cartilage Induced by Unloading Condition Accelerates Histological Progression of Osteoarthritis in a Post-traumatic Rat Model

Cartilage ◽  
2020 ◽  
pp. 194760352098235
Author(s):  
Ikufumi Takahashi ◽  
Taro Matsuzaki ◽  
Hiroshi Kuroki ◽  
Masahiro Hoso
Keyword(s):  
Articular Cartilage ◽  
Rat Model ◽  
Immunohistochemical Analysis ◽  
Research Society ◽  
Hindlimb Unloading ◽  
Male Rats ◽  
Hindlimb Suspension ◽  
Disuse Atrophy ◽  
Osteoarthritis Research Society ◽  
Post Traumatic

Objective The study aim was to evaluate the histological relationship between osteoarthritis (OA) and articular cartilage in disuse atrophy induced by hindlimb unloading in a post-traumatic OA rat model. Design Forty male rats were divided into the 4 following experimental groups: control, hindlimb suspension (HS), OA induced by destabilization of the medial meniscus (OA), and OA induction after hindlimb suspension (HS-OA). Histological changes in the articular cartilage of the tibia were evaluated by the Osteoarthritis Research Society International (OARSI) scores and histomorphometrical analyses at 2, 4, and 8 weeks after OA induction. Results We confirmed that disuse atrophy of the articular cartilage was caused by thinning of the articular cartilage and the decrease in matrix staining for the nonloading period of 4 weeks. The OARSI scores and histomorphological analyses revealed that OA progressed significantly wider and deeper in the HS-OA group than in the OA group over time. In the sham group, disuse atrophy of the articular cartilage recovered at 2 weeks after reloading. Conclusions This study revealed that OA progressed faster in cartilage atrophy than in normal articular cartilage. Further studies are required for investigating the mechanisms of disuse atrophy of cartilage and its association with OA using the biochemical and immunohistochemical analysis.

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