scholarly journals Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis

2015 ◽  
Vol 75 (3) ◽  
pp. 627-631 ◽  
Author(s):  
Thibault Bouderlique ◽  
Karuna K Vuppalapati ◽  
Phillip T Newton ◽  
Lei Li ◽  
Björn Barenius ◽  
...  
Keyword(s):  
Cell Death ◽  
Research Society ◽  
Targeted Deletion ◽  
Nucleotidyl Transferase ◽  
Medial Meniscectomy ◽  
Age Related ◽  
Osteoarthritis Research Society ◽  
Post Traumatic ◽  
Safranin O ◽  
And Control

ObjectivesIt has been suggested that the lysosomal recycling process called macro-autophagy plays a role in osteoarthritis development. We thus decided to genetically ablate the autophagy-indispensable Atg5 gene specifically in chondrocytes and analyse the development of osteoarthritis upon aging and in a post-traumatic model.MethodsMice lacking the Atg5 gene in their chondrocytes (Atg5cKO) were generated by crossing Atg5-floxed mice with transgenic mice that expressed cre recombinase driven by the collagen type 2 promoter. Animals were analysed at the age of 2, 6 and 12 months for age-related osteoarthritis or underwent mini-open partial medial meniscectomy at 2 months of age and were analysed 1 or 2 months after surgery. We evaluated osteoarthritis using the Osteoarthritis Research Society International (OARSI) scoring on safranin-O-stained samples. Cell death was evaluated by terminal deoxy-nucleotidyl-transferase-mediated deoxy-UTP nick end labelling (TUNEL) and by immunostaining of cleaved caspases.ResultsWe observed the development of osteoarthritis in Atg5cKO mice with aging including fibrillation and loss of proteoglycans, which was particularly severe in males. The ablation of Atg5 was associated with an increased cell death as assessed by TUNEL, cleaved caspase 3 and cleaved caspase 9. Surprisingly, no difference in the development of post-traumatic osteoarthritis was observed between Atg5cKO and control mice.ConclusionsAutophagy protects from age-related osteoarthritis by facilitating chondrocyte survival.

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.

Aging Cartilage in Wild-Type Mice: An Observational Study

Cartilage ◽  
2020 ◽  
pp. 194760352092671
Author(s):  
Joulnar Akoum ◽  
Khadija Tahiri ◽  
Marie-Thérèse Corvol ◽  
Didier Borderie ◽  
François Étienne ◽  
...  
Keyword(s):  
Walking Speed ◽  
Articular Surface ◽  
Type Ii Collagen ◽  
Research Society ◽  
Male Mice ◽  
Wild Type ◽  
Calcified Cartilage ◽  
Age Related ◽  
Wild Type Male ◽  
Osteoarthritis Research Society

Objective To describe the spontaneous evolution of age-related changes affecting knee joint articular cartilage, walking speed and a serum biomarker of cartilage remodeling in C57BL/6-JRj wild-type male mice. Design Histological changes were assessed by the Osteoarthritis Research Society International (OARSI) score (0=normal, 6=vertical clefts/erosion to the calcified cartilage extending >75% of the articular surface) in newborn, 1-week- and 1-, 3-, 6-, 9- and 12-month-old C57BL/6-JRj wild-type male mice, walking speed by the Locotronic system, and serum C-terminal telopeptide of type II collagen (CTX-II) content by ELISA in 1-, 3-, 6-, and 9-month-old C57BL/6-JRj wild-type male mice. Results Mean (SD) OARSI score significantly increased from 0.2 (0.3) to 1.3 (0.6) ( p=0.03) between 1 and 3 months of age and from 1.3 (0.6) to 3.3 (0.6) ( p=0.04) between 3 and 6 months of age. Mean walking speed was stable between 1 and 6 months of age but significantly decreased from 11.4 (1.8) to 3.2 (0.8) cm.s-1 ( p=0.03) between 6 and 9 months of age. Serum CTX-II content was maximal at 1 month of age, then decreased from 12.2 (8.5) to 2.4 (8.4) pg/ml ( p=0.02) between 1 and 3 months of age, remaining low and stable thereafter. Conclusions C57BL/6-JRj wild-type male mice showed continuously increasing osteoarthritic changes but delayed decreasing walking speed with age. These variations were maximal between 3 and 9 months of age. Maximal serum CTX-II content preceded these changes.

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 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.

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

2018 ◽  
Vol 77 (10) ◽  
pp. 1524-1534 ◽  
Author(s):  
Haiyan Zhang ◽  
Chuangxin Lin ◽  
Chun Zeng ◽  
Zhenyu Wang ◽  
Hua Wang ◽  
...  
Keyword(s):  
Cartilage Damage ◽  
Research Society ◽  
M1 Macrophages ◽  
Myeloid Lineage ◽  
Synovial Macrophage ◽  
Osteoarthritis Research Society ◽  
Synovial Tissues ◽  
Experimental Osteoarthritis ◽  
And Control

ObjectivesTo investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA).MethodsSynovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA.ResultsM1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of β-catenin signalling in chondrocytes.ConclusionsSynovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment.

Oxidative Stress, Ocular Disease and Diabetes Retinopathy

2019 ◽  
Vol 24 (40) ◽  
pp. 4726-4741 ◽  
Author(s):  
Orathai Tangvarasittichai ◽  
Surapon Tangvarasittichai
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Protein Modification ◽  
Morphological Changes ◽  
Corneal Dystrophy ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Retinal Light Damage ◽  
Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

scholarly journals Implication of ferroptosis in aging

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maryam Mazhar ◽  
Ahmad Ud Din ◽  
Hamid Ali ◽  
Guoqiang Yang ◽  
Wei Ren ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Accelerated Aging ◽  
Underlying Mechanism ◽  
Toxic Chemicals ◽  
Whole Body ◽  
Regulated Cell Death ◽  
Age Related ◽  
The Subject ◽  
Conventional Cell

AbstractLife is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

scholarly journals Treadmill Exercise after Controlled Abnormal Joint Movement Inhibits Cartilage Degeneration and Synovitis

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 303
Author(s):  
Yuichiro Oka ◽  
Kenij Murata ◽  
Kaichi Ozone ◽  
Takuma Kano ◽  
Yuki Minegishi ◽  
...  
Keyword(s):  
Treadmill Exercise ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Therapeutic Effects ◽  
Joint Movement ◽  
Knee Oa ◽  
Anterior Cruciate ◽  
Safranin O ◽  
Walking Group

Cartilage degeneration is the main pathological component of knee osteoarthritis (OA), but no effective treatment for its control exists. Although exercise can inhibit OA, the abnormal joint movement with knee OA must be managed to perform exercise. Our aims were to determine how controlling abnormal joint movement and treadmill exercise can suppress cartilage degeneration, to analyze the tissues surrounding articular cartilage, and to clarify the effect of treatment. Twelve-week-old ICR mice (n = 24) underwent anterior cruciate ligament transection (ACL-T) surgery on their right knees and were divided into three groups as follows: ACL-T, animals in the walking group subjected to ACL-T; controlled abnormal joint movement (CAJM), and CAJM with exercise (CAJM + Ex) (n = 8/group). Walking-group animals were subjected to treadmill exercise 6 weeks after surgery, including walking for 18 m/min, 30 min/day, 3 days/week for 8 weeks. Safranin-O staining, hematoxylin-eosin staining, and immunohistochemical staining were performed. The OARSI (Osteoarthritis research Society international) score was lower in the CAJM group than in the ACL-T group and was even lower in the CAJM + Ex group. The CAJM group had a lower meniscal injury score than the ACL-T group, and the CAJM + Ex group demonstrated a less severe synovitis than the ACL-T and CAJM groups. The observed difference in the perichondrium tissue damage score depending on the intervention method suggests different therapeutic effects, that normalizing joint motion can solve local problems in the knee joint, and that the anti-inflammatory effect of treadmill exercise can suppress cartilage degeneration.

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