scholarly journals Chronic Circadian Rhythm Disturbance Accelerates Knee Cartilage Degeneration in Rats Accompanied by the Activation of the Canonical Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaopeng Song ◽  
Tianwen Ma ◽  
Hailong Hu ◽  
Mingchao Zhao ◽  
Hui Bai ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Signaling Pathway ◽  
Early Stage ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Matrix Degradation ◽  
Knee Cartilage ◽  
Rhythm Disturbance ◽  
Gsk 3Β ◽  
Canonical Wnt

With the gradual deepening of understanding of systemic health and quality of life, the factors affecting osteoarthritis (OA) are not limited to mechanical injury, metabolic abnormality, age and obesity, etc., but circadian rhythm, which plays a non-negligible role in human daily life. The purpose of this study was to explore the molecular mechanism of chronic circadian rhythm disturbance (CRD) inducing cartilage OA-like degeneration. Rats with the anterior cruciate ligament excision transection (ACLT) were used to establish the early-stage OA model (6-week). The light/dark (LD) cycle shifted 12 h per week for 22 weeks in order to establish a chronic CRD model. BMAL1 knockdown (KD) and Wnt/β-catenin pathway inhibition were performed in chondrocytes. The contents of proinflammatory factors and OA biomarkers in serum and chondrocyte secretions were detected by ELISA. Pathological and immunohistochemical staining of articular cartilage indicated the deterioration of cartilage. WB and qPCR were used to evaluate the relationship between matrix degradation and the activation of Wnt/β-catenin signaling pathway in chondrocytes. We found that chronic CRD could cause OA-like pathological changes in knee cartilage of rats, accelerating cartilage matrix degradation and synovial inflammation. The expression of MMP-3, MMP-13, ADAMTS-4, and β-catenin increased significantly; BMAL1, Aggrecan, and COL2A1 decreased significantly in either LD-shifted cartilage or BMAL1-KD chondrocytes. The expression of β-catenin and p-GSK-3β elevated, while p-β-catenin and GSK-3β diminished. The inhibitor XAV-939 was able to mitigated the increased inflammation produced by transfected siBMAL1. Our study demonstrates that chronic CRD disrupts the balance of matrix synthesis and catabolic metabolism in cartilage and chondrocytes, and it is related to the activation of the canonical Wnt/β-catenin signaling pathway.

scholarly journals A divergent canonical WNT-signaling pathway regulates microtubule dynamics

2004 ◽  
Vol 164 (2) ◽  
pp. 243-253 ◽  
Author(s):  
Lorenza Ciani ◽  
Olga Krylova ◽  
Matthew J. Smalley ◽  
Trevor C. Dale ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Canonical Wnt Signaling ◽  
Microtubule Stability ◽  
Gsk 3Β ◽  
Canonical Wnt

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

scholarly journals Comparison of early-stage changes of osteoarthritis in cartilage and subchondral bone between two different rat models

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8934 ◽  
Author(s):  
Yutao Yang ◽  
Peiran Li ◽  
Songsong Zhu ◽  
Ruiye Bi
Keyword(s):  
Subchondral Bone ◽  
Early Stage ◽  
Cruciate Ligament ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
The Elderly ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Bone Change ◽  
Subchondral Bone Change

Osteoarthritis (OA) is a chronic degenerative joint disease and the major cause of joint pain and disability in the elderly. It is mainly characterized by articular cartilage degradation and subchondral bone remodeling. There are two main types of OA: natural occurring OA and secondary OA, mainly associated with aging and trauma, respectively. In this study, we established two OA models in rat knee joints to simulate the two types of OA, using the type II collagenase injection (CI) and anterior cruciate ligament transection (ACLT), respectively. After intervention for 2–6 weeks, cartilage and subchondral bone changes were detected in histological staining, immunochemistry, and micro-CT. Results showed that both models with typical pathology changes of OA were successfully induced, while the development and severity of OA process in the models were different. In ACLT rats, the cartilage damage was milder, lasted for a shorter time, and subchondral bone reconstruction occurred earlier, compared with the changes in CI rats. The cartilage damage was secondary to subchondral bone change in ACLT rats, while subchondral bone change was secondary to cartilage degeneration in CI rats. In conclusion, the interaction between cartilage and subchondral bone is different between the natural-occurring and secondary OA models. These two models not only suggest potential different mechanisms of the two types of OA, but also provide new directions for OA treatment and prevention.

scholarly journals Chlorogenic Acids Inhibit Adipogenesis: Implications of Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Mengting Liu ◽  
Jian Qin ◽  
Jing Cong ◽  
Yubin Yang
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Fatty Acid Synthase ◽  
Adipocyte Differentiation ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Ppar Γ ◽  
Gsk 3Β ◽  
Canonical Wnt

In our previous in vitro study, we found that chlorogenic acid (CGA) inhibited adipocyte differentiation and triglyceride (TG) accumulation, but the underlying mechanism is still unclear. Accumulative genetic evidence supports that canonical Wnt signaling is a key modulator on adipogenesis. Methods. In this study, 3T3-L1 cells were induced adipogenic differentiation and then treated with CGA. We investigate the effect of CGA in inhibiting adipogenesis and evaluate its role in modulating Wnt10b (wingless integration1 10b), β-catenin, glycogen synthase kinase-3β (GSK-3β), and peroxisome proliferator-activated receptor γ (PPAR-γ) involved in the Wnt (wingless integration1)/β-catenin signaling pathway. Results. The result showed that after CGA treatment, lipid accumulation and TG level decreased significantly in 3T3-L1 cells, indicating that CGA could inhibit adipogenesis. In addition, CGA repressed the induction of adipocyte differentiation biomarkers as PPAR-γ, adipocyte protein 2 (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL), and the secretion of GSK-3β in a dose-dependent manner upregulated the expression of β-catenin and Wnt10b both in gene and protein levels. Moreover, CGA induced phosphorylation of GSK-3β and promoted the accumulation of free cytosolic β-catenin in 3T3-L1 adipocytes. Conclusion. Overall, these findings gave us the implications that CGA inhibits adipogenesis via the canonical Wnt signaling pathway.

scholarly journals Polydatin Protects Against Articular Cartilage Degeneration by Regulating Autophagy Mediated by AMPK/Mtor Signaling Pathway

2021 ◽  
Author(s):  
Zhengcong Ye ◽  
Chun He ◽  
Pengzheng Yu ◽  
Guoping Cao ◽  
Qinrong Shen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Rat Model ◽  
Cell Model ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Mtor Signaling ◽  
Tunel Staining ◽  
Mtor Signaling Pathway ◽  
Proliferation And Apoptosis

Abstract Background: Knee osteoarthritis (KOA) is one of the leading causes of disability, and its etiopathogenesis is not completely understood. Polydatin has the potential effect on the treatment of KOA, but the mechanism is not clear.Methods: After an KOA rat model was established by anterior cruciate ligament transection, KOA rats were treated with polydatin (4 mg/kg) for 30 days. Subsequently, cartilage tissues were collected from rats and detected by HE, TUNEL staining and Western blotting to evaluate the pathological damage, apoptosis and autophagy activity. Then, human chondrocyte C28/I2 cells were stimulated by LPS to induce a KOA model in vitro, and the effects of polydatin on the C28/I2 cell viability, apoptosis and autophagy were also detected. In addition, the mechanism of polydatin on KOA in C28/I2 cells was investigated, and the effect of an AMPK inhibitor (Dorsomorphin 2HCl) on the proliferation and apoptosis of polydatin administrated-cells were also detected. Results: After treated with polydatin, the pathological damage of rat cartilage tissues were ameliorated, cells apoptosis was inhibited and autophagy was activated in KOA rats. Meanwhile, polydatin also ameliorated the proliferation and apoptosis of C28/I2 cells, the expression of autophagy-related proteins, LC3II/LC3I, Beclin-1, and p-AMPK/AMPK were up-regulated, p-mTOR/mTOR was down-regulated by polydatin in C28/I2 cells. Interestingly, relative results showed that the improvement effect of polydatin on LPS-sdtimulated-C28/I2 cells was blocked by AMPK/mTOR inhibitor, Dorsomorphin 2HCl. Conclusion: Our research showed that polydatin reduces apoptosis and activate autophagy both in a rat model of KOA and C28/I2 cell model by AMPK/mTOR signaling pathway, which provides the basis for further investigations into the potential therapeutic impact of polydatin in KOA.

Mechanoregulated Bone Remodeling May Explain Bone Structural Changes Observed in Osteoarthritis

2010 ◽  
Author(s):  
L. G. E. Cox ◽  
C. C. van Donkelaar ◽  
B. van Rietbergen ◽  
K. Ito
Keyword(s):  
Subchondral Bone ◽  
Structural Changes ◽  
Early Stage ◽  
Cruciate Ligament ◽  
Disease Process ◽  
Cartilage Degeneration ◽  
Bone Diseases ◽  
Strenuous Exercise ◽  
Metabolic Bone Diseases ◽  
Bone Changes

Osteoarthritis (OA) affects both the articular cartilage and the subchondral bone. It is a complicated disease, associated with conditions varying from obesity and strenuous exercise to joint malalignment, anterior cruciate ligament (ACL) injury, and even metabolic bone diseases. Patients suffer from chronic joint pain and limitation of motion, and no cure is yet available. For many years, medical therapies have been focused on cartilage, because bone changes were thought not to play a major role in the OA disease process. However, it has been shown that bone changes occur in an early stage of OA, and that alterations to subchondral bone can lead to cartilage degeneration [1]. Therefore, currently the bone is considered as a therapeutic target as well.

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