scholarly journals Pink1-Mediated Chondrocytic Mitophagy Contributes to Cartilage Degeneration in Osteoarthritis

2019 ◽  
Vol 8 (11) ◽  
pp. 1849 ◽  
Author(s):  
Hyo Jung Shin ◽  
Hyewon Park ◽  
Nara Shin ◽  
Hyeok Hee Kwon ◽  
Yuhua Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Articular Chondrocytes ◽  
Mitochondrial Fission ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Osteoarthritic Cartilage ◽  
Monosodium Iodoacetate ◽  
Biochemical Mechanisms ◽  
Related Proteins

Cartilage loss is a central event in the pathogenesis of osteoarthritis (OA), though other than mechanical loading, the biochemical mechanisms underlying OA pathology remain poorly elucidated. We investigated the role of Pink1-mediated mitophagy in mitochondrial fission, a crucial process in OA pathogenesis. We used a monosodium iodoacetate (MIA)-induced rodent model of OA, which inhibits the activity of articular chondrocytes, leading to disruption of glycolytic energy metabolism and eventual cell death. The OA rat cartilage exhibits significant induction of autophagy-related proteins LC3B and p62, similar to human osteoarthritic cartilage. Moreover, expression of Pink1 and Parkin proteins were also increased in OA. Here, we confirm that Pink1-mediated mitophagy leads to cell death in chondrocytes following MIA treatment, while deficiency in Pink1 expression was associated with decreased cartilage damage and pain behaviors in MIA-induced OA. Finally, we found that autophagy and mitophagy-related genes are highly expressed in human osteoarthritic cartilage. These results indicate that OA is a degenerative condition associated with mitophagy, and suggest that targeting the Pink1 pathway may provide a therapeutic avenue for OA treatment.

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.

Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Michael Coronado ◽  
Giovanni Fajardo ◽  
Kim Nguyen ◽  
Mingming Zhao ◽  
Kristina Bezold Kooiker ◽  
...  
Keyword(s):  
Cell Death ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Adrenergic Receptor ◽  
Mitochondrial Fission ◽  
Physiological Adaptation ◽  
Mitochondrial Fragmentation ◽  
Energetic Demand ◽  
Adaptation To Exercise

Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.

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 Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Li Zhang ◽  
Runlin Xing ◽  
Zhengquan Huang ◽  
Nongshan Zhang ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Knee Osteoarthritis ◽  
Synovial Fibroblasts ◽  
Vital Role ◽  
Aseptic Inflammation ◽  
Synovial Macrophage ◽  
The Right ◽  
Related Proteins ◽  
Sirius Red

Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

scholarly journals Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovanna Nalesso ◽  
Anne-Sophie Thorup ◽  
Suzanne Elizabeth Eldridge ◽  
Anna De Palma ◽  
Amanpreet Kaur ◽  
...  
Keyword(s):  
Medial Meniscus ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Cartilage Damage ◽  
Regenerative Processes ◽  
Cartilage Homeostasis ◽  
Calmodulin Kinase ◽  
Wnt Ligands ◽  
Pharmacological Blockade

AbstractWNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been associated with the onset of different diseases. Here we investigated the role of the WNT/Calcium Calmodulin Kinase II (CaMKII) pathway in osteoarthritis. We identified Heme Oxygenase I (HMOX1) and Sox-9 as specific markers of the WNT/CaMKII signalling in articular chondrocytes through a microarray analysis. We showed that the expression of the activated form of CaMKII, phospho-CaMKII, was increased in human and murine osteoarthritis and the expression of HMOX1 was accordingly reduced, demonstrating the activation of the pathway during disease progression. To elucidate its function, we administered the CaMKII inhibitor KN93 to mice in which osteoarthritis was induced by resection of the anterior horn of the medial meniscus and of the medial collateral ligament in the knee joint. Pharmacological blockade of CaMKII exacerbated cartilage damage and bone remodelling. Finally, we showed that CaMKII inhibition in articular chondrocytes upregulated the expression of matrix remodelling enzymes alone and in combination with Interleukin 1. These results suggest an important homeostatic role of the WNT/CaMKII signalling in osteoarthritis which could be exploited in the future for therapeutic purposes.

scholarly journals Acupuncture Delays Cartilage Degeneration through Upregulating SIRT1 Expression in Rats with Osteoarthritis

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Hui Liu ◽  
Tingting Zhang ◽  
Min Liu ◽  
Chunhong Wang ◽  
Jinfeng Yan
Keyword(s):  
Cartilage Degeneration ◽  
Cartilage Matrix ◽  
Enzyme Linked Immunosorbent Assay ◽  
Matrix Degradation ◽  
Matrix Synthesis ◽  
Sirt1 Expression ◽  
Tnf Α ◽  
Related Proteins ◽  
And Cartilage

Silent mating type information regulation 2 homolog 1 (SIRT1) has been reported to inhibit osteoarthritic gene expression in chondrocytes. Here, efforts in this study were made to unveil the specific role of SIRT1 in the therapy of acupuncture on cartilage degeneration in osteoarthritis (OA). Specifically, OA was established by the anterior cruciate ligament transection method in the right knee joint of rats, subsequent to which acupuncture was performed on two acupoints. Injection with shSIRT1 sequence–inserted lentiviruses was conducted to investigate the role of SIRT1 in acupuncture-mediated OA. Morphological changes and cell apoptosis in rat OA cartilages were examined by safranin-O staining and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay, respectively. The serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-2 in OA rats were assessed by enzyme-linked immunosorbent assay (ELISA). The expressions of SIRT1, cartilage matrix degradation-related proteins (matrix metalloproteinase (MMP)-9 and ADAMTS5), NF-κB signaling-related markers (p-p65/p65 and p-IκBα/IκBα), and cartilage matrix synthesis-related proteins (collagen II and aggrecan) in the OA cartilage were analyzed by western blot. As a result, acupuncture counteracted OA-associated upregulation of TNF-α, IL-2, cartilage matrix degradation-related proteins, and NF-κB signaling-related markers, morphological damage, apoptosis, SIRT1 downregulation, and loss of cartilage matrix synthesis-related proteins in rat articular cartilages. SIRT1 silencing reversed acupuncture-induced counteractive effects on the aforementioned OA-associated phenomena (except apoptosis, the experiment regarding which under SIRT1 silencing was not performed). Collectively, acupuncture inhibited chondrocyte apoptosis, inflammation, NF-κB signaling activation, and cartilage matrix degradation by upregulating SIRT1 expression to delay OA-associated cartilage degeneration.

scholarly journals Inhibiting the Mitochondrial Fission Machinery Does Not Prevent Bax/Bak-Dependent Apoptosis

2006 ◽  
Vol 26 (20) ◽  
pp. 7397-7408 ◽  
Author(s):  
Philippe A. Parone ◽  
Dominic I. James ◽  
Sandrine Da Cruz ◽  
Yves Mattenberger ◽  
Olivier Donzé ◽  
...  
Keyword(s):  
Cell Death ◽  
Morphological Changes ◽  
Mitochondrial Fission ◽  
Mitochondrial Network ◽  
Mitochondrial Fragmentation ◽  
Caspase Inhibition ◽  
Precise Role

ABSTRACT Apoptosis, induced by a number of death stimuli, is associated with a fragmentation of the mitochondrial network. These morphological changes in mitochondria have been shown to require proteins, such as Drp1 or hFis1, which are involved in regulating the fission of mitochondria. However, the precise role of mitochondrial fission during apoptosis remains elusive. Here we report that inhibiting the fission machinery in Bax/Bak-mediated apoptosis, by down-regulating of Drp1 or hFis1, prevents the fragmentation of the mitochondrial network and partially inhibits the release of cytochrome c from the mitochondria but fails to block the efflux of Smac/DIABLO. In addition, preventing mitochondrial fragmentation does not inhibit cell death induced by Bax/Bak-dependent death stimuli, in contrast to the effects of Bcl-xL or caspase inhibition. Therefore, the fission of mitochondria is a dispensable event in Bax/Bak-dependent apoptosis.

Role of IL-1 on Aggrecanase and COX-2 Gene Expression of Meniscal Explants Following Dynamic Compression

2010 ◽  
Author(s):  
Megan L. Killian ◽  
Barbara Zielinska ◽  
Tammy L. Haut Donahue
Keyword(s):  
Gene Expression ◽  
Prostaglandin E2 ◽  
Dynamic Compression ◽  
Cartilage Damage ◽  
Matrix Degradation ◽  
Osteoarthritic Cartilage ◽  
Interleukin 1Α ◽  
Cox 2

The menisci within the knee likely respond to adverse loading conditions, leading to aggravated cartilage damage and fissuring [1]. Upregulation of catabolic molecules such as interleukin-1α (IL-1α), metalloproteinases (MMPs), aggrecanases (ADAMTS-4 and -5), and cyclooxygenase-2 (COX-2), as well as release of proteoglycans [2], have been shown in vitro for meniscal explants following dynamic loading [3]. A crucial event in matrix degradation is the loss of aggrecan, caused by the ADAMTS family [4]. In osteoarthritic cartilage, IL-1 has been shown to influence COX-2 activity, leading to increased synthesis of prostaglandin E2 and subsequent proteinase activity [5].

scholarly journals Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

2021 ◽  
Vol 8 ◽  
Author(s):  
Qing-Yuan Gao ◽  
Hai-Feng Zhang ◽  
Jun Tao ◽  
Zhi-Teng Chen ◽  
Chi-Yu Liu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Mitochondrial Fission ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Impairment ◽  
Related Proteins ◽  
Tgf Β1

Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-β1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-β1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-β1-induced CF activation. The TGF-β1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-β1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.

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