scholarly journals Overexpression of Mig-6 in Limb Mesenchyme Leads to Accelerated Osteoarthritis in Mice

2019 ◽  
Author(s):  
Melina Rodrigues Bellini ◽  
Michael Andrew Pest ◽  
Jae-Wook Jeong ◽  
Frank Beier
Keyword(s):  
Articular Cartilage ◽  
Molecular Mechanisms ◽  
Cartilage Degeneration ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Synovial Joint ◽  
Egfr Signaling ◽  
Bone Thickness ◽  
Developmental Effects ◽  
And Control

ABSTRACTBackgroundMitogen-inducible gene 6 (Mig-6) is a tumour suppressor gene that is also associated with the development of osteoarthritis (OA)-like disorder. Recent evidence from our lab and others showed that cartilage-specific Mig-6 knockout (KO) mice develop chondro-osseous nodules, along with increased articular cartilage thickness and enhanced EGFR signaling in the articular cartilage. Here, we evaluate the phenotype of mice with skeletal-specific overexpression of Mig-6.MethodsSynovial joint tissues of the knee were assessed in 12 and 36 weeks-old skeleton-specific Mig-6 overexpressing (Mig-6over/over) and control animals using histological stains, immunohistochemistry, semi-quantitative OARSI scoring, and microCT for skeletal morphometry. Measurement of articular cartilage and subchondral bone thickness were also performed using histomorphometry.ResultsOur results show only subtle developmental effects of Mig-6 overexpression. However, male Mig-6over/over mice show accelerated cartilage degeneration at 36 weeks of age, in both medial and lateral compartments of the knee. Immunohistochemistry for SOX9 and PRG4 showed decreased staining in Mig-6over/over mice relative to controls, providing potential molecular mechanisms for the observed effects.ConclusionOverexpression of Mig-6 in articular cartilage causes no major developmental phenotype but results in accelerated development of OA during aging. These data demonstrate that precise regulation of the Mig-6/EGFR pathway is critical for joint homeostasis.

scholarly journals Early patellofemoral articular cartilage degeneration in a rat model of patellar instability is associated with activation of the NF-κB signaling pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wei Lin ◽  
Huijun Kang ◽  
Yike Dai ◽  
Yingzhen Niu ◽  
Guangmin Yang ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Patellofemoral Joint ◽  
Patellar Instability ◽  
Cartilage Degeneration ◽  
Control Group ◽  
And Control ◽  
Articular Cartilage Degeneration ◽  
And Cartilage

Abstract Background Patellar instability (PI) often increases the possibility of lateral patellar dislocation and early osteoarthritis. The molecular mechanism of early articular cartilage degeneration during patellofemoral osteoarthritis (PFOA) still requires further investigation. However, it is known that the NF-κB signaling pathway plays an important role in articular cartilage degeneration. The aim of this study was to investigate the relationship between the NF-κB signaling pathway and patellofemoral joint cartilage degeneration. Methods We established a rat model of PI-induced PFOA. Female 4-week-old Sprague-Dawley rats (n = 120) were randomly divided into two groups: the PI (n = 60) and control group (n = 60). The distal femurs of the PI and control group were isolated and compared 4, 8, and 12 weeks after surgery. The morphological structure of the trochlear cartilage and subchondral bone were evaluated by micro-computed tomography and histology. The expression of NF-κB, matrix metalloproteinase (MMP)-13, collagen X, and TNF-ɑ were evaluated by immunohistochemistry and quantitative polymerase chain reaction. Results In the PI group, subchondral bone loss and cartilage degeneration were found 4 weeks after surgery. Compared with the control group, the protein and mRNA expression of NF-κB and TNF-ɑ were significantly increased 4, 8, and 12 weeks after surgery in the PI group. In addition, the markers of cartilage degeneration MMP-13 and collagen X were more highly expressed in the PI group compared with the control group at different time points after surgery. Conclusions This study has demonstrated that early patellofemoral joint cartilage degeneration can be caused by PI in growing rats, accompanied by significant subchondral bone loss and cartilage degeneration. In addition, the degeneration of articular cartilage may be associated with the activation of the NF-κB signaling pathway and can deteriorate with time as a result of PI.

scholarly journals Effect of intraarticular injection of chondroitin sulfate into synovial joint elements in an experiment

2020 ◽  
pp. 84-89
Author(s):  
V. I. Nikolaev ◽  
D. A. Zinovkin ◽  
A. A. Tretyakov
Keyword(s):  
Articular Cartilage ◽  
Chondroitin Sulfate ◽  
Subchondral Bone ◽  
Growth Zone ◽  
Epiphyseal Cartilage ◽  
Knee Joints ◽  
Joint Control ◽  
Synovial Joint ◽  
Cell Content ◽  
And Control

Objective: to study morphological and morphometric changes in the epiphysis bone in a rat during the intra-articular injection of chondroitin sulfate (CS). Mаteriаl аnd methods. The object of the study was the knee joints of 36 Wistar rats. CS injections at a dose of 0.05 ml were performed once a week into one of the knee joints (experimental joint), and isotonic NaCl solution at the same volume was injected into the opposite joint (control joint). The animals in the number of 12 units were withdrawn from the experiment on the 7th, 14th, and 21st days, which corresponded to one week after one-, two-and three-fold intra-articular injections of HC and 0.9 % NaCl. The isolated knee joints were placed in a decalcifying liquid, then were fixed in 10% neutral buffered formalin. 4 micron histological sections were stained with hematoxylin and eosin. The morphometric analysis assessed the thickness of hyaline articular cartilage, the thickness of the epiphysis growth zone cartilage, and the cell content of the subchondral bone. Results. The study of the thickness of the articular cartilage, the growth zone of epiphyseal cartilage and the cellular composition of the subchondral bone has showed a statistically significant dynamic increase in these indicators after the 2nd and 3rd intra-articular injections of CS. The assessment of the thickness of the articular cartilage on the 21st day found some statistically significant differences between the experimental and control groups (p < 0.0001), the thickness of the epiphyseal cartilage had increased significantly by that time (p < 0.0001), and the cell content of bone marrow showed statistically significant differences (p = 0.002). Conclusion. The obtained data testify to a pronounced regenerative effect of CS, injected intra-articularly into articular cartilage.

scholarly journals Playing Tag with HIF: The VHL Story

2002 ◽  
Vol 2 (3) ◽  
pp. 131-135 ◽  
Author(s):  
Sherri K. Leung ◽  
Michael Ohh
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
E3 Ubiquitin Ligase ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets theαsubunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF), which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

scholarly journals Epigenetic silencing of the XAF1 gene is mediated by the loss of CTCF binding

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Georgina Victoria-Acosta ◽  
Karla Vazquez-Santillan ◽  
Luis Jimenez-Hernandez ◽  
Laura Muñoz-Galindo ◽  
Vilma Maldonado ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Epigenetic Silencing ◽  
Ctcf Binding ◽  
Open Chromatin ◽  
Cpg Dinucleotide

Abstract XAF1 is a tumour suppressor gene that compromises cell viability by modulating different cellular events such as mitosis, cell cycle progression and apoptosis. In cancer, the XAF1 gene is commonly silenced by CpG-dinucleotide hypermethylation of its promoter. DNA demethylating agents induce transcriptional reactivation of XAF1, sensitizing cancer cells to therapy. The molecular mechanisms that mediate promoter CpG methylation have not been previously studied. Here, we demonstrate that CTCF interacts with the XAF1 promoter in vivo in a methylation-sensitive manner. By transgene assays, we demonstrate that CTCF mediates the open-chromatin configuration of the XAF1 promoter, inhibiting both CpG-dinucleotide methylation and repressive histone posttranslational modifications. In addition, the absence of CTCF in the XAF1 promoter inhibits transcriptional activation induced by well-known apoptosis activators. We report for the first time that epigenetic silencing of the XAF1 gene is a consequence of the loss of CTCF binding.

scholarly journals Early Patellofemoral Articular Cartilage Degeneration in a Rat Model of Patellar Instability is Associated with Activation of the NF-κB Signaling Pathway

2020 ◽  
Author(s):  
Wei Lin ◽  
Huijun Kang ◽  
Yike Dai ◽  
Yingzhen Niu ◽  
Guangmin Yang ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Patellofemoral Joint ◽  
Patellar Instability ◽  
Cartilage Degeneration ◽  
Control Group ◽  
And Control ◽  
Articular Cartilage Degeneration ◽  
And Cartilage

Abstract Background: Patellar instability (PI) often increases the possibility of lateral patellar dislocation and early osteoarthritis. The molecular mechanism of early articular cartilage degeneration during patellofemoral osteoarthritis (PFOA) still requires further investigation. However, it is known that the NF-κB signaling pathway plays an important role in articular cartilage degeneration. The aim of this study was to investigate the relationship between the NF-κB signaling pathway and patellofemoral joint cartilage degeneration. Methods: We established a rat model of PI-induced PFOA. Female 4-week-old Sprague-Dawley rats (n=120) were randomly divided into two groups: the PI (n=60) and control group (n=60). The distal femurs of the PI and control group were isolated and compared 4, 8, and 12 weeks after surgery. The morphological structure of the trochlear cartilage and subchondral bone were evaluated by micro-computed tomography and histology. The expression of NF-κB, matrix metalloproteinase (MMP)-13, collagen X, and TNF-ɑ were evaluated by immunohistochemistry and quantitative polymerase chain reaction. Results: In the PI group, subchondral bone loss and cartilage degeneration were found 4 weeks after surgery. Compared with the control group, the protein and mRNA expression of NF-κB and TNF-ɑ were significantly increased 4, 8, and 12 weeks after surgery in the PI group. In addition, the markers of cartilage degeneration MMP-13 and collagen X were more highly expressed in the PI group compared with the control group at different time points after surgery.Conclusions: This study has demonstrated that early patellofemoral joint cartilage degeneration can be caused by PI in growing rats, accompanied by significant subchondral bone loss and cartilage degeneration. In addition, the degeneration of articular cartilage may be associated with the activation of the NF-κB signaling pathway and can deteriorate with time as a result of PI.

scholarly journals EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

2016 ◽  
Vol 113 (50) ◽  
pp. 14360-14365 ◽  
Author(s):  
Haoruo Jia ◽  
Xiaoyuan Ma ◽  
Wei Tong ◽  
Basak Doyran ◽  
Zeyang Sun ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
High Surface ◽  
Cartilage Degeneration ◽  
Superficial Layer ◽  
Joint Disease ◽  
Egfr Signaling ◽  
Superficial Zone ◽  
Cartilage Surface ◽  
Healthy Cartilage ◽  
Important Regulator

Osteoarthritis (OA) is the most common joint disease, characterized by progressive destruction of the articular cartilage. The surface of joint cartilage is the first defensive and affected site of OA, but our knowledge of genesis and homeostasis of this superficial zone is scarce. EGFR signaling is important for tissue homeostasis. Immunostaining revealed that its activity is mostly dominant in the superficial layer of healthy cartilage but greatly diminished when OA initiates. To evaluate the role of EGFR signaling in the articular cartilage, we studied a cartilage-specific Egfr-deficient (CKO) mouse model (Col2-Cre EgfrWa5/flox). These mice developed early cartilage degeneration at 6 mo of age. By 2 mo of age, although their gross cartilage morphology appears normal, CKO mice had a drastically reduced number of superficial chondrocytes and decreased lubricant secretion at the surface. Using superficial chondrocyte and cartilage explant cultures, we demonstrated that EGFR signaling is critical for maintaining the number and properties of superficial chondrocytes, promoting chondrogenic proteoglycan 4 (Prg4) expression, and stimulating the lubrication function of the cartilage surface. In addition, EGFR deficiency greatly disorganized collagen fibrils in articular cartilage and strikingly reduced cartilage surface modulus. After surgical induction of OA at 3 mo of age, CKO mice quickly developed the most severe OA phenotype, including a complete loss of cartilage, extremely high surface modulus, subchondral bone plate thickening, and elevated joint pain. Taken together, our studies establish EGFR signaling as an important regulator of the superficial layer during articular cartilage development and OA initiation.

scholarly journals Mechanical Intervention for Maintenance of Cartilage and Bone

2011 ◽  
Vol 4 ◽  
pp. CMAMD.S6982 ◽  
Author(s):  
Hui B. Sun ◽  
Luis Cardoso ◽  
Hiroki Yokota
Keyword(s):  
Articular Cartilage ◽  
Bone Remodeling ◽  
Mechanical Loading ◽  
Growth And Development ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Joint Motion ◽  
Synovial Joint ◽  
Mechanical Intervention ◽  
Stimulation Of

Mechanical loading provides indispensible stimuli for growth and development of the articular cartilage and bone. Interestingly, depending on loading conditions loads applied to the joint can be beneficial as well as harmful to skeletal maintenance and remodeling. Moderate loads to the synovial joint, for instance, suppress the expression levels of matrix metallproteinases (MMPs), while loads above a threshold tend to increase their destructive activities. This report focuses on two recently developed loading modalities from animal studies, joint motion and joint loading. Their unique characteristics and potential usages for maintenance of the articular cartilage and stimulation of bone remodeling are reviewed. Also described are biophysical and molecular mechanisms which likely are responsible for the load-driven maintenance of cartilage and bone, and a possibility of developing load-mediated treatments of osteoporosis and osteoarthritis.

scholarly journals Early Patellofemoral Articular Cartilage Degeneration in a Rat Model of Patellar Instability is Associated with Activation of the NF-κB Signaling Pathway

2020 ◽  
Author(s):  
Wei Lin ◽  
Yike Dai ◽  
Guangmin Yang ◽  
Jinghui Niu ◽  
Ming Li ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Patellofemoral Joint ◽  
Patellar Instability ◽  
Cartilage Degeneration ◽  
Control Group ◽  
And Control ◽  
Articular Cartilage Degeneration ◽  
And Cartilage

Abstract Background: Patellar instability (PI) often increases the possibility of lateral patellar dislocation and early osteoarthritis. The molecular mechanism of early articular cartilage degeneration during patellofemoral osteoarthritis (PFOA) still requires further investigation. However, it is known that the NF-κB signaling pathway plays an important role in articular cartilage degeneration. The aim of this study was to investigate the relationship between the NF-κB signaling pathway and patellofemoral joint cartilage degeneration. Methods: We established a rat model of PI-induced PFOA. Female 4-week-old Sprague-Dawley rats (n=120) were randomly divided into two groups: the PI (n=60) and control group (n=60). The distal femurs of the PI and control group were isolated and compared 4, 8, and 12 weeks after surgery. The morphological structure of the trochlear cartilage and subchondral bone were evaluated by micro-computed tomography and histology. The expression of NF-κB, matrix metalloproteinase (MMP)-13, collagen X, and TNF-ɑ were evaluated by immunohistochemistry and quantitative polymerase chain reaction. Results: In the PI group, subchondral bone loss and cartilage degeneration were found 4 weeks after surgery. Compared with the control group, the protein and mRNA expression of NF-κB and TNF-ɑ were significantly increased 4, 8, and 12 weeks after surgery in the PI group. In addition, the markers of cartilage degeneration MMP-13 and collagen X were more highly expressed in the PI group compared with the control group at different time points after surgery.Conclusions: This study has demonstrated that early patellofemoral joint cartilage degeneration can be caused by PI in growing rats, accompanied by significant subchondral bone loss and cartilage degeneration. In addition, the degeneration of articular cartilage may be associated with the activation of the NF-κB signaling pathway and can deteriorate with time as a result of PI.

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