scholarly journals Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin-Xin Zhang ◽  
Shi-Hao He ◽  
Xu Liang ◽  
Wei Li ◽  
Tian-Fang Li ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cellular Senescence ◽  
Articular Chondrocytes ◽  
Cartilage Degradation ◽  
Cell Senescence ◽  
Joint Disease ◽  
Epigenetic Alterations ◽  
New Agents ◽  
Key Factor ◽  
Long Time

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

scholarly journals The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis

2020 ◽  
Author(s):  
CR Coveney ◽  
L Zhu ◽  
J Miotla-Zarebska ◽  
B Stott ◽  
I Parisi ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cell Biology ◽  
Articular Chondrocytes ◽  
Skeletal Development ◽  
Cartilage Degradation ◽  
Cartilage Thickness ◽  
Tissue Growth ◽  
Calcified Cartilage ◽  
Health And Disease

AbstractMechanical forces are known to drive cellular signalling programmes in cartilage development, health, and disease. Proteins of the primary cilium, implicated in mechanoregulation, control cartilage formation during skeletal development, but their role in post-natal cartilage is unknown. Ift88fl/fl and AggrecanCreERT2 mice were crossed to create a cartilage specific inducible knockout mouse AggrecanCreERT2;Ift88fl/fl. Tibial articular cartilage thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. In situ cell biology was investigated by immunohistochemistry (IHC) and qPCR of micro-dissected cartilage. OA was induced by destabilisation of the medial meniscus (DMM). Some mice were provided with exercise wheels in their cage. Deletion of IFT88 resulted in a reduction in medial articular cartilage thickness (atrophy) during adolescence from 102.57μm, 95% CI [94.30, 119.80] in control (Ift88fl/fl) to 87.36μm 95% CI [81.35, 90.97] in AggrecanCreERT2;Ift88fl/fl by 8-weeks p<0.01, and adulthood (104.00μm, 95% CI [100.30, 110.50] in Ift88fl/fl to 89.42μm 95% CI [84.00, 93.49] in AggrecanCreERT2;Ift88fl/fl, 34-weeks, p<0.0001) through a reduction in calcified cartilage. Thinning in adulthood was associated with spontaneous cartilage degradation. Following DMM, AggrecanCreERT2;Ift88fl/fl mice had increased OA (OARSI scores at 12 weeks Ift88fl/fl = 22.08 +/− 9.30, and AggrecanCreERT2;Ift88fl/fl = 29.83 +/− 7.69). Atrophy was not associated with aggrecanase-mediated destruction or chondrocyte hypertrophy. Ift88 expression positively correlated with Tcf7l2 and connective tissue growth factor. Cartilage thickness was restored in AggrecanCreERT2;Ift88fl/fl by voluntary wheel exercise. Our results demonstrate that ciliary IFT88 regulates cartilage thickness and is chondroprotective, potentially through modulating mechanotransduction pathways in articular chondrocytes.

scholarly journals Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 927 ◽  
Author(s):  
Szu-Yu Chien ◽  
Chun-Hao Tsai ◽  
Shan-Chi Liu ◽  
Chien-Chung Huang ◽  
Tzu-Hung Lin ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Subchondral Bone ◽  
Bone Destruction ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Bone Morphogenetic Protein 2 ◽  
Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

scholarly journals New Therapeutic Strategies for Osteoarthritis by Targeting Sialic Acid Receptors

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 637 ◽  
Author(s):  
Paula Carpintero-Fernandez ◽  
Marta Varela-Eirin ◽  
Alessandra Lacetera ◽  
Raquel Gago-Fuentes ◽  
Eduardo Fonseca ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Ex Vivo ◽  
Molecular Model ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Novel Therapy ◽  
Human Cartilage ◽  
Sialic Acid Receptors ◽  
Cartilage Breakdown

Osteoarthritis (OA) is the most common degenerative joint disease characterized by articular cartilage degradation and joint degeneration. The articular cartilage is mainly formed by chondrocytes and a collagen-proteoglycan extracellular matrix that contains high levels of glycosylated proteins. It was reported that the shift from glycoproteins containing α-2,6-linked sialic acids to those that contain α-2,3 was associated with the onset of common types of arthritis. However, the pathophysiology of α-2,3-sialylation in cartilage has not been yet elucidated. We show that cartilage from osteoarthritic patients expresses high levels of the α-2,3-sialylated transmembrane mucin receptor, known as podoplanin (PDPN). Additionally, the Maackia amurensis seed lectin (MASL), that can be utilized to target PDPN, attenuates the inflammatory response mediated by NF-kB activation in primary chondrocytes and protects human cartilage breakdown ex vivo and in an animal model of arthritis. These findings reveal that specific lectins targeting α-2,3-sialylated receptors on chondrocytes might effectively inhibit cartilage breakdown. We also present a computational 3D molecular model for this interaction. These findings provide mechanistic information on how a specific lectin could be used as a novel therapy to treat degenerative joint diseases such as osteoarthritis.

scholarly journals Extracellular Vesicles and Their Potential Significance in the Pathogenesis and Treatment of Osteoarthritis

2021 ◽  
Vol 14 (4) ◽  
pp. 315
Author(s):  
Anne-Mari Mustonen ◽  
Petteri Nieminen
Keyword(s):  
Articular Cartilage ◽  
Extracellular Vesicles ◽  
Articular Chondrocytes ◽  
Functional Limitations ◽  
Expression Patterns ◽  
Biologically Active ◽  
Joint Disease ◽  
Cartilage Defects ◽  
Matrix Deposition ◽  
And Cartilage

Osteoarthritis (OA) is a chronic joint disease characterized by inflammation, gradual destruction of articular cartilage, joint pain, and functional limitations that eventually lead to disability. Join tissues, including synovium and articular cartilage, release extracellular vesicles (EVs) that have been proposed to sustain joint homeostasis as well as to contribute to OA pathogenesis. EVs transport biologically active molecules, and OA can be characterized by altered EV counts and composition in synovial fluid. Of EV cargo, specific non-coding RNAs could have future potential as diagnostic biomarkers for early OA. EVs may contribute to the propagation of inflammation and cartilage destruction by transporting and enhancing the production of inflammatory mediators and cartilage-degrading proteinases. In addition to inducing OA-related gene expression patterns in synoviocytes and articular chondrocytes, EVs can induce anti-OA effects, including increased extracellular matrix deposition and cartilage protection. Especially mesenchymal stem cell-derived EVs can alleviate intra-articular inflammation and relieve OA pain. In addition, surgically- or chemically-induced cartilage defects have been repaired with EV therapies in animal models. While human clinical trials are still in the future, the potential of actual cures to OA by EV products is very promising.

scholarly journals Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondrocytes via the TLR4-ERK1/2-c-Jun Signaling Pathway

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2500
Author(s):  
Yi-Ting Chen ◽  
Chih-Chien Wang ◽  
Chia-Pi Cheng ◽  
Feng-Cheng Liu ◽  
Chian-Her Lee ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Arthritis ◽  
Articular Chondrocytes ◽  
Saturated Fatty Acids ◽  
Signal Transduction Pathway ◽  
Cartilage Degradation ◽  
Cartilage Matrix ◽  
Human Articular Chondrocytes ◽  
Cox 2 ◽  
Interleukin 26

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1β can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.

scholarly journals Down-regulation of microRNA-203a suppresses IL-1β-induced inflammation and cartilage degradation in human chondrocytes through Smad3 signaling

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Yongbo An ◽  
Guang Wan ◽  
Jingang Tao ◽  
Mingxing Cui ◽  
Qinglan Zhou ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Response ◽  
In Vitro Model ◽  
Joint Inflammation ◽  
Cartilage Degradation ◽  
Inhibitory Effects ◽  
Key Factor ◽  
Ecm Degradation ◽  
Vitro Model

Abstract Osteoarthritis (OA) is a chronic and prevalent degenerative musculoskeletal disorder, which is characterized by articular cartilage degradation and joint inflammation. MicroRNA-203a (miR-203a) has been shown to be involved in multiple pathological processes during OA, but little is known about its function in chondrocyte extracellular matrix (ECM) degradation. In the present study, we aimed to elucidate the effects of miR-203a on articular cartilage degradation and joint inflammation. We observed that the miR-203a level was significantly up-regulated in OA tissues and in an in vitro model of OA, respectively. Inhibition of miR-203a significantly alleviated the interleukin (IL)-1β-induced inflammatory response and ECM degradation in chondrocytes. Moreover, mothers against decapentaplegic homolog 3 (Smad3), a key factor in maintaining chondrocyte homeostasis, was identified as a putative target of miR-203a in chondrocytes. More importantly, inhibition of Smad3 impaired the inhibitory effects of the miR-203a on IL-1β-induced inflammatory response and ECM degradation. Collectively, these results demonstrated that miR-203a may contribute to articular cartilage degradation of OA by targeting Smad3, suggesting a novel therapeutic target for the treatment of OA.

scholarly journals Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

2021 ◽  
Author(s):  
Xiaohao Wu ◽  
Yumei Lai ◽  
Sheng Chen ◽  
Chunlei Zhou ◽  
Chu Tao ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Structural Changes ◽  
Articular Chondrocytes ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Mitochondrial Oxidative Stress ◽  
Adhesion Protein ◽  
Genetic Ablation ◽  
Focal Adhesion Protein

Osteoarthritis (OA) is an aging-related degenerative joint disease, which has no cure partly due to limited understanding of its pathological mechanism(s). Here we report that the focal adhesion protein Kindlin-2, but not Kindlin-1 or -3, is highly expressed in articular chondrocytes of the hyaline cartilage, which is dramatically decreased in the degenerated articular cartilage of aged mice and patients with OA. Inducible deletion of Kindlin-2 in chondrocytes at adult stage leads to spontaneous OA and much severe OA lesions in the mice receiving the surgery of destabilization of the medial meniscus. Mechanistically, Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3 in articular chondrocytes, leading to Runx2-mediated chondrocyte hypertrophic differentiation and catabolism. In vivo, systemic pharmacological blockade of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and ECM-degrading enzymes and limits OA deteriorations caused by Kindlin-2 deficiency. Furthermore, genetic inactivation of Runx2 in chondrocytes reverses structural changes and OA lesions caused by Kindlin-2 deletion without down-regulating p-Stat3 in articular chondrocytes. Of translational significance, intraarticular injection of Kindlin-2-expressing adeno-associated virus decelerates progression of aging- and instability-induced knee joint OA in mice. Collectively, we identify a novel pathway comprising of Kindlin-2, Stat3 and Runx2 in articular chondrocytes responsible for maintaining integrity of the articular cartilage and define a potential therapeutic target for OA.

Review about structure and evaluation of reactivators of Acetylcholinesterase inhibited with neurotoxic organophosphorus compounds

2020 ◽  
Vol 27 ◽  
Author(s):  
José Daniel Figueroa-Villar ◽  
Elaine C. Petronilho ◽  
Kamil Kuca ◽  
Tanos C. C. Franca
Keyword(s):  
Organophosphorus Compounds ◽  
Chemical Warfare Agents ◽  
Nerve Impulse ◽  
Limited Capacity ◽  
New Agents ◽  
Long Time ◽  
Warfare Agents ◽  
Comprehensive Search ◽  
Pharmacology And Toxicology ◽  
The Many

Background: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the organophosphates (OPs) capable of restricting the enzyme acetylcholinesterase (AChE), which in turn controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relative long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the blood-brain barrier (BBB). This fact compromises their capacity of reactivating AChE inside the nervous system. Methods: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. Results: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents’ development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. Conclusion: To develop these new agents it is necessary the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics); organic synthesis; spectroscopic methodologies; biology, biochemical and biophysical information; medicinal chemistry, pharmacology and toxicology.

scholarly journals The Jekyll and Hyde of Cellular Senescence in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 208
Author(s):  
Dilara Demirci ◽  
Bengisu Dayanc ◽  
Fatma Aybuke Mazi ◽  
Serif Senturk
Keyword(s):  
Cancer Cell ◽  
Cellular Senescence ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Adverse Outcomes ◽  
Cell Senescence ◽  
Great Promise

Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.

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