scholarly journals Effects of rAAV-Mediated sox9 Overexpression on the Biological Activities of Human Osteoarthritic Articular Chondrocytes in Their Intrinsic Three-Dimensional Environment

2019 ◽  
Vol 8 (10) ◽  
pp. 1637 ◽  
Author(s):  
Oliver Daniels ◽  
Janina Frisch ◽  
Jagadeesh K. Venkatesan ◽  
Ana Rey-Rico ◽  
Gertrud Schmitt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Articular Chondrocytes ◽  
Biological Activities ◽  
Three Dimensional ◽  
Type Ii Collagen ◽  
Osteoarthritic Cartilage ◽  
Cellular Processes ◽  
Therapeutic Sequence ◽  
Progressive Disorder ◽  
Significant Production

Gene therapy for osteoarthritis offers powerful, long-lasting tools that are well adapted to treat such a slow, progressive disorder, especially those therapies based on the clinically adapted recombinant adeno-associated viral (rAAV) vectors. Here, we examined the ability of an rAAV construct carrying a therapeutic sequence for the cartilage-specific SOX9 transcription factor to modulate the phenotype of human osteoarthritic articular chondrocytes compared with normal chondrocytes in a three-dimensional environment where the cells are embedded in their extracellular matrix. Successful sox9 overexpression via rAAV was noted for at least 21 days, leading to the significant production of major matrix components (proteoglycans, type-II collagen) without affecting the proliferation of the cells, while the cells contained premature hypertrophic processes relative to control conditions (reporter rAAV-lacZ application, absence of vector treatment). These findings show the value of using rAAV to adjust the osteoarthritic phenotype when the chondrocytes are confined in their inherently altered environment and the possibility of impacting key cellular processes via gene therapy to remodel human osteoarthritic cartilage lesions.

scholarly journals α-Catenin Inhibits β-Catenin-T-cell Factor/Lymphoid Enhancing Factor Transcriptional Activity and Collagen Type II Expression in Articular Chondrocytes through Formation of Gli3R·α-Catenin·β-Catenin Ternary Complex

2012 ◽  
Vol 287 (15) ◽  
pp. 11751-11760 ◽  
Author(s):  
Jinseol Rhee ◽  
Je-Hwang Ryu ◽  
Jin-Hong Kim ◽  
Churl-Hong Chun ◽  
Jang-Soo Chun
Keyword(s):  
T Cell ◽  
Ternary Complex ◽  
Transcriptional Activity ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Osteoarthritic Cartilage ◽  
T Cell Factor ◽  
Collagen Expression ◽  
Enhancing Factor

Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/β-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits β-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of β-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and β-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to β-catenin by α-catenin. The resulting inhibition of β-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on β-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate β-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·β-catenin, mediates Ihh-dependent activation of Wnt/β-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to β-catenin to inhibit β-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of β-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased β-catenin transcriptional activity during osteoarthritic cartilage destruction.

Dysregulation of HOX as a Potential Therapeutic Target in Breast Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ji-Yeon Lee ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Hox Genes ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Genome Structure ◽  
Control Cell ◽  
Three Dimensional ◽  
Cellular Processes ◽  
Hox Protein

: HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer; they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs, embedded within the HOX cluster, and the role of these molecules in breast cancer have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

scholarly journals Naphthalimide-Containing BP100 Leads to Higher Model Membranes Interactions and Antimicrobial Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 542
Author(s):  
Gustavo Penteado Battesini Carretero ◽  
Greice Kelle Viegas Saraiva ◽  
Magali Aparecida Rodrigues ◽  
Sumika Kiyota ◽  
Marcelo Porto Bemquerer ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Biological Activities ◽  
Biological Effects ◽  
Membrane Surface ◽  
Helical Structure ◽  
Helical Conformation ◽  
Property A ◽  
Cellular Processes ◽  
Double Stranded Dna ◽  
Low Toxicity

In a large variety of organisms, antimicrobial peptides (AMPs) are primary defenses against pathogens. BP100 (KKLFKKILKYL-NH2), a short, synthetic, cationic AMP, is active against bacteria and displays low toxicity towards eukaryotic cells. BP100 acquires a α-helical conformation upon interaction with membranes and increases membrane permeability. Despite the volume of information available, the action mechanism of BP100, the selectivity of its biological effects, and possible applications are far from consensual. Our group synthesized a fluorescent BP100 analogue containing naphthalimide linked to its N-terminal end, NAPHT-BP100 (Naphthalimide-AAKKLFKKILKYL-NH2). The fluorescence properties of naphthalimides, especially their spectral sensitivity to microenvironment changes, are well established, and their biological activities against transformed cells and bacteria are known. Naphthalimide derived compounds are known to interact with DNA disturbing related processes as replication and transcription, and used as anticancer agents due to this property. A wide variety of techniques were used to demonstrate that NAPHT-BP100 bound to and permeabilized zwitterionic POPC and negatively charged POPC:POPG liposomes and, upon interaction, acquired a α-helical structure. Membrane surface high peptide/lipid ratios triggered complete permeabilization of the liposomes in a detergent-like manner. Membrane disruption was driven by charge neutralization, lipid aggregation, and bilayer destabilization. NAPHT-BP100 also interacted with double-stranded DNA, indicating that this peptide could also affect other cellular processes besides causing membrane destabilization. NAPHT-BP100 showed increased antibacterial and hemolytic activities, compared to BP100, and may constitute an efficient antimicrobial agent for dermatological use. By conjugating BP100 and naphthalimide DNA binding properties, NAPHT-BP100 bound to a large extent to the bacterial membrane and could more efficiently destabilize it. We also speculate that peptide could enter the bacteria cell and interact with its DNA in the cytoplasm.

scholarly journals Three-Dimensional Zirconia-Based Scaffolds for Load-Bearing Bone-Regeneration Applications: Prospects and Challenges

Materials ◽  
2021 ◽  
Vol 14 (12) ◽  
pp. 3207
Author(s):  
Kumaresan Sakthiabirami ◽  
Vaiyapuri Soundharrajan ◽  
Jin-Ho Kang ◽  
Yunzhi Peter Yang ◽  
Sang-Won Park
Keyword(s):  
Bone Regeneration ◽  
Biological Activities ◽  
Three Dimensional ◽  
In Vivo Studies ◽  
High Mechanical Strength ◽  
Real World Applications ◽  
3D Fabrication ◽  
Dental Applications

The design of zirconia-based scaffolds using conventional techniques for bone-regeneration applications has been studied extensively. Similar to dental applications, the use of three-dimensional (3D) zirconia-based ceramics for bone tissue engineering (BTE) has recently attracted considerable attention because of their high mechanical strength and biocompatibility. However, techniques to fabricate zirconia-based scaffolds for bone regeneration are in a stage of infancy. Hence, the biological activities of zirconia-based ceramics for bone-regeneration applications have not been fully investigated, in contrast to the well-established calcium phosphate-based ceramics for bone-regeneration applications. This paper outlines recent research developments and challenges concerning numerous three-dimensional (3D) zirconia-based scaffolds and reviews the associated fundamental fabrication techniques, key 3D fabrication developments and practical encounters to identify the optimal 3D fabrication technique for obtaining 3D zirconia-based scaffolds suitable for real-world applications. This review mainly summarized the articles that focused on in vitro and in vivo studies along with the fundamental mechanical characterizations on the 3D zirconia-based scaffolds.

scholarly journals The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model

2021 ◽  
Vol 22 (14) ◽  
pp. 7247
Author(s):  
Jana Riegger ◽  
Julia Baumert ◽  
Frank Zaucke ◽  
Rolf E. Brenner
Keyword(s):  
Biosynthetic Pathway ◽  
Ex Vivo ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Uridine Diphosphate ◽  
Cell Protection ◽  
Ex Vivo Model ◽  
Human Cartilage ◽  
Hexosamine Biosynthetic Pathway ◽  
Cellular Processes

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

Behavior of Human Articular Chondrocytes Derived from Nonarthritic and Osteoarthritic Cartilage in a Collagen Matrix

2005 ◽  
Vol 11 (5-6) ◽  
pp. 877-886 ◽  
Author(s):  
Ronald Dorotka ◽  
Ulrich Bindreiter ◽  
Patrick Vavken ◽  
Stefan Nehrer
Keyword(s):  
Articular Chondrocytes ◽  
Collagen Matrix ◽  
Human Articular Chondrocytes ◽  
Osteoarthritic Cartilage

Assessment of α-calcium sulfate hemihydrate/nanocellulose composite bone graft material for bone healing in a rabbit femoral condyle model

2021 ◽  
Vol 11 (9) ◽  
pp. 1497-1504
Author(s):  
Jinlong Liu ◽  
Yicai Zhang ◽  
Lin Qiu ◽  
Yujuan Zhang ◽  
Bin Gao
Keyword(s):  
Bone Graft ◽  
Calcium Sulfate ◽  
Biological Activities ◽  
Femoral Condyle ◽  
Three Dimensional ◽  
Graft Material ◽  
Bone Graft Material ◽  
Calcium Sulfate Hemihydrate ◽  
Composite Bone

The material properties of nanocellulose (NC) can effectively enhance the structural stability of composite materials. However, the research related to NC/α-calcium sulfate hemihydrate (CSH) composites is largely lacking. In this paper, we explore the combination of these two materials and determine their elaborate biological activities in vivo. Using α-CSH as the matrix, the composite bone graft materials were produced according to different proportions of NC. Then the mechanical strength of the composite bone graft was measured, and the results were analyzed by X-ray diffraction and scanning electron microscopy (SEM). To conduct the material in vivo evaluation, 0% (CN0) and 0.75% (CN0.75) NC/α-CSH composite bone graft materials were implanted into a femoral condyle defect model. The results indicated that NC could significantly enhance the mechanical properties of α-CSH. The SEM analysis indicated that the NC shuttled between the crystal gaps and formed a three-dimensional network structure, which was firmly combined with the crystal structure. Meanwhile, the CN0.75 scaffold remained at 12 weeks postoperation, which provided a long-term framework for new bone formation. Overall, our findings demonstrate that, with a 0.75% NC/α-CSH composite demonstrating good potential as a bone graft material for clinical bone grafting.

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