P123 Cell death in a rabbit model for post-traumatic cartilage degeneration and osteoarthritis

Abstract Background Emerging evidence suggests that microRNAs (miRs) are associated with the progression of osteoarthritis (OA). In this study, the role of exosomal miR-136-5p derived from mesenchymal stem cells (MSCs) in OA progression is investigated and the potential therapeutic mechanism explored. Methods Bone marrow mesenchymal stem cells (BMMSCs) and their exosomes were isolated from patients and identified. The endocytosis of chondrocytes and the effects of exosome miR-136-5p on cartilage degradation were observed and examined by immunofluorescence and cartilage staining. Then, the targeting relationship between miR-136-5p and E74-like factor 3 (ELF3) was analyzed by dual-luciferase report assay. Based on gain- or loss-of-function experiments, the effects of exosomes and exosomal miR-136-5p on chondrocyte migration were examined by EdU and Transwell assay. Finally, a mouse model of post-traumatic OA was developed to evaluate effects of miR-136-5p on chondrocyte degeneration in vivo. Results In the clinical samples of traumatic OA cartilage tissues, we detected increased ELF3 expression, and reduced miR-136-5p expression was determined. The BMMSC-derived exosomes showed an enriched level of miR-136-5p, which could be internalized by chondrocytes. The migration of chondrocyte was promoted by miR-136-5p, while collagen II, aggrecan, and SOX9 expression was increased and MMP-13 expression was reduced. miR-136-5p was verified to target ELF3 and could downregulate its expression. Moreover, the expression of ELF3 was reduced in chondrocytes after internalization of exosomes. In the mouse model of post-traumatic OA, exosomal miR-136-5p was found to reduce the degeneration of cartilage extracellular matrix. Conclusion These data provide evidence that BMMSC-derived exosomal miR-136-5p could promote chondrocyte migration in vitro and inhibit cartilage degeneration in vivo, thereby inhibiting OA pathology, which highlighted the transfer of exosomal miR-136-5p as a promising therapeutic strategy for patients with OA.

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Therapeutic Potential of Kappa Opioid Agonists

Pharmaceuticals ◽

10.3390/ph12020095 ◽

2019 ◽

Vol 12 (2) ◽

pp. 95 ◽

Cited By ~ 8

Author(s):

Tyler C. Beck ◽

Matthew A. Hapstack ◽

Kyle R. Beck ◽

Thomas A. Dix

Keyword(s):

Therapeutic Potential ◽

Inflammatory Diseases ◽

Cartilage Degeneration ◽

Review Article ◽

Research Articles ◽

Original Research ◽

Kappa Opioid ◽

Opioid Agonists ◽

Novel Drugs ◽

Post Traumatic

Many original research articles have been published that describe findings and outline areas for the development of kappa-opioid agonists (KOAs) as novel drugs; however, a single review article that summarizes the broad potential for KOAs in drug development does not exist. It is well-established that KOAs demonstrate efficacy in pain attenuation; however, KOAs also have proven to be beneficial in treating a variety of novel but often overlapping conditions including cardiovascular disease, pruritus, nausea, inflammatory diseases, spinal anesthesia, stroke, hypoxic pulmonary hypertension, multiple sclerosis, addiction, and post-traumatic cartilage degeneration. This article summarizes key findings of KOAs and discusses the untapped therapeutic potential of KOAs in the treatment of many human diseases.

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microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213629 ◽

2018 ◽

Vol 78 (1) ◽

pp. 111-121 ◽

Cited By ~ 18

Author(s):

Akihiro Nakamura ◽

Yoga Raja Rampersaud ◽

Sayaka Nakamura ◽

Anirudh Sharma ◽

Fanxing Zeng ◽

...

Keyword(s):

Cell Death ◽

Antisense Oligonucleotides ◽

Apoptotic Cell ◽

Cartilage Degeneration ◽

Apoptotic Cell Death ◽

Knee Joints ◽

Protective Effects ◽

Knee Oa ◽

Articular Cartilage Degeneration

ObjectivesWe recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration.MethodsWe used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression.ResultsmiR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects.ConclusionsOur data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.

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Ameliorating Glycosaminoglycan (GAG) Loss and Cell Death in Articular Cartilage Following Single-Impact Loading

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176542 ◽

2007 ◽

Author(s):

Roman M. Natoli ◽

Kyriacos A. Athanasiou

Keyword(s):

Extracellular Matrix ◽

Cell Death ◽

Articular Cartilage ◽

Impact Loading ◽

Biomechanical Properties ◽

Cartilage Explants ◽

Single Impact ◽

Igf I ◽

Post Traumatic ◽

Bioactive Agents

Impact loading of articular cartilage leads to post-traumatic osteoarthritis (OA) through its effects on the cells and extracellular matrix (ECM) of the tissue. Studies have shown the level of impact or injurious compression correlates with increased cell death, degradation of the ECM, and detrimental changes in biomechanical properties [1]. Recently, several bioactive agents, such as P188 and IGF-I, have shown promising results by reducing cell death following injurious compression of cartilage explants [2, 3].

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Disturbances in Metabolic Pathways and the Identification of a Potential Biomarker Panel for Early Cartilage Degeneration in a Rabbit Anterior Cruciate Ligament Transection Model

Cartilage ◽

10.1177/1947603520921434 ◽

2020 ◽

pp. 194760352092143

Author(s):

Yiwen Hu ◽

Qian Wu ◽

Yang Qiao ◽

Peng Zhang ◽

Wentao Dai ◽

...

Keyword(s):

Anterior Cruciate Ligament ◽

Cruciate Ligament ◽

Pearson Correlation ◽

Rabbit Model ◽

Cartilage Degeneration ◽

Anterior Cruciate Ligament Transection ◽

Sham Surgery ◽

Potential Biomarker ◽

Anterior Cruciate ◽

Potential Biomarkers

Objective This study aimed to assess the association between synovial fluid (SF) metabolites and magnetic resonance imaging (MRI) measurements of cartilage biochemical composition to identify potential SF biomarkers for detecting the early onset of cartilage degeneration in a rabbit model. Methods Both knees of 12 New Zealand White rabbits were used. The anterior cruciate ligament transection (ACLT) model was performed on right knees, and the sham surgery on left knees. MRI UTE-T2* scanning and SF sample collection were performed on ACLT knees at 4 and 8 weeks postsurgery and on sham surgery knees at 4 weeks postsurgery. Ultra-performance liquid chromatography–mass spectrometry and multivariate statistical analysis were used to distinguish samples in three groups. Pathway and receiver operating characteristic analyses were utilized to identify potential metabolite biomarkers. Results There were 12 knees in sham surgery models, 11 in ACLT models at 4 weeks postsurgery, and 10 in ACLT models at 8 weeks postsurgery. UTE-T2* values for the lateral tibia cartilage showed significant decreases over the study period. Levels of 103 identified metabolites in SF were markedly different among three groups. Furthermore, 24 metabolites were inversely correlated with UTE-T2* values of the lateral tibia cartilage, while hippuric acid was positively correlated with UTE-T2* values of the lateral tibia cartilage. Among 25 potential markers, N1-acetylspermidine, 2-amino-1,3,4-octadecanetriol, l-phenylalanine, 5-hydroxy-l-tryptophan, and l-tryptophan were identified as potential biomarkers with high area under the curve values and Pearson correlation coefficients. Conclusion Five differential metabolites in SF were found as potential biomarkers for the early detection of cartilage degeneration in the rabbit ACLT model.

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