Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation

2021 ◽  
Author(s):  
Kentaro Takeuchi ◽  
Hiroyasu Ogawa ◽  
Norishige Kuramitsu ◽  
Keisuke Akaike ◽  
Atsushi Goto ◽  
...  
Keyword(s):  
Cartilage Degeneration ◽  
Mmp13 Expression

The Effect of Total Meniscectomy versus Caudal Pole Hemimeniscectomy on the Stifle Joint of the Sheep

1999 ◽  
Vol 12 (02) ◽  
pp. 56-63 ◽  
Author(s):  
C. R. Bellenger ◽  
P. Ghosh ◽  
Y. Numata ◽  
C. Little ◽  
D. S. Simpson
Keyword(s):  
Tissue Culture ◽  
Articular Cartilage ◽  
Fibrous Tissue ◽  
Cartilage Degeneration ◽  
Medial Compartment ◽  
Proteoglycan Synthesis ◽  
Stifle Joint ◽  
Medial Meniscectomy ◽  
Tibial Condyle ◽  
Articular Cartilage Degeneration

SummaryTotal medial meniscectomy and caudal pole hemimeniscectomy were performed on the stifle joints of twelve sheep. The two forms of meniscectomy produced a comparable degree of postoperative lameness that resolved within two weeks of the operations. After six months the sheep were euthanatised and the stifle joints examined. Fibrous tissue that replaced the excised meniscus in the total meniscectomy group did not cover as much of the medial tibial condyle as the residual cranial pole and caudal fibrous tissue observed following hemimeniscectomy. The articular cartilage from different regions within the joints was examined for gross and histological evidence of degeneration. Analyses of the articular cartilage for water content, glycosaminoglycan composition and DNA content were performed. The proteoglycan synthesis and release from explanted articular cartilage samples in tissue culture were also measured. There were significant pathological changes in the medial compartment of all meniscectomised joints. The degree of articular cartilage degeneration that was observed following total meniscectomy and caudal pole meniscectomy was similar. Caudal pole hemimeniscectomy, involving transection of the meniscus, causes the same degree of degeneration of the stifle joint that occurs following total meniscectomy.The effect of total medial meniscectomy versus caudal pole hemimeniscectomy on the stifle joint of sheep was studied experimentally. Six months after the operations gross pathology, histopathology, cartilage biochemical analysis and the rate of proteoglycan synthesis in tissue culture were used to compare the articular cartilage harvested from the meniscectomised joints. Degeneration of the articular cartilage from the medial compartment of the joints was present in both of the groups. Caudal pole hemimeniscectomy induces a comparable degree of articular cartilage degeneration to total medial meniscectomy in the sheep stifle joint.

MOLECULAR CONTROL OF ARTICULAR CARTILAGE DEGENERATION BY TRANSFORMING GROWTH FACTOR ALPHA

2008 ◽  
Vol 31 (4) ◽  
pp. 2
Author(s):  
Tom Appleton ◽  
Shirine Usmani ◽  
John Mort ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Articular Cartilage ◽  
Growth Factor ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Cartilage Degeneration ◽  
Signalling Pathways ◽  
Transforming Growth Factor Alpha ◽  
Factor Alpha ◽  
Articular Cartilage Degeneration

Background: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We previously identified increased expression of transforming growth factor alpha (TGF?) and chemokine (C-C motif) ligand 2 (CCL2) in articular cartilage from a rat modelof OA (1,2). We subsequently reported that TGF? signalling modified chondrocyte cytoskeletal organization, increased catabolic and decreased anabolic gene expression and suppressed Sox9. Due to other roles in chondrocytes, we hypothesized that the effects ofTGF? on chondrocytes are mediated by Rho/ROCK and MEK/ERK signaling pathways. Methods: Primary cultures of chondrocytes and articularosteochondral explants were treated with pharmacological inhibitors of MEK1/2(U0126), ROCK (Y27632), Rho (C3), p38 MAPK (SB202190) and PI3K (LY294002) to elucidate pathway involvement. Results: Using G-LISA we determined that stimulation of primary chondrocytes with TGF? activates RhoA. Reciprocally, inhibition of RhoA/ROCK but not other signalling pathways prevents modification of the actin cytoskeleton in responseto TGF?. Inhibition of MEK/ERKsignaling rescued suppression of anabolic gene expression by TGF? including SOX9 mRNA and protein levels. Inhibition of MEK/ERK, Rho/ROCK, p38 MAPK and PI3K signalling pathways differentially controlled the induction of MMP13 and TNF? gene expression. TGF? also induced expression of CCL2 specifically through MEK/ERK activation. In turn, CCL2 treatment induced the expression of MMP3 and TNF?. Finally, we assessed cartilage degradation by immunohistochemical detection of type II collagen cleavage fragments generated by MMPs. Blockade of RhoA/ROCK and MEK/ERK signalling pathways reduced the generation of type IIcollagen cleavage fragments in response to TGF? stimulation. Conclusions: Rho/ROCK signalling mediates TGF?-induced changes inchondrocyte morphology, while MEK/ERK signalling mediates the suppression ofSox9 and its target genes, and CCL2 expression. CCL2, in turn, induces the expression of MMP3 and TNF?, two potent catabolic factors known to be involved in OA. These pathways may represent strategic targets for interventional approaches to treating cartilage degeneration in osteoarthritis. References: 1. Appleton CTG et al. Arthritis Rheum 2007;56:1854-68. 2. Appleton CTG et al. Arthritis Rheum 2007; 56:3693-705.

scholarly journals POS0393 FIBRIN DEPOSITION IS AN ACTIVE TRIGGER OF CARTILAGE DEGENERATION IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 426.1-426
Author(s):  
T. Hügle ◽  
S. Nasi ◽  
D. Ehirchiou ◽  
P. Omoumi ◽  
A. So ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Cartilage Explants ◽  
Fibrin Deposition ◽  
Qrt Pcr ◽  
Catabolic Genes ◽  
Key Factor ◽  
Calcific Deposits

Background:Fibrin(ogen) maintains inflammation in various disorders but has never been linked to cartilage damage in rheumatoid arthritis (RA) or other forms of inflammatory arthritis.Objectives:To investigate the role of fibrin deposition on cartilage integrity in arthritis.Methods:Fibrin deposition on knee cartilage was analyzed by immunohistochemistry in RA patients and in murine adjuvant-induced arthritis (AIA). In chondrocytes, fibrinogen expression (Fgα, Fgβ, Fgγ) and procoagulant activity were evaluated by qRT-PCR and turbidimetry respectively. Fibrin-induced catabolic genes were assessed by qRT-PCR in chondrocytes. Fibrin-mediated chondro-synovial adhesion (CSA) with subsequent cartilage tears was studied in co-cultures of human RA cartilage with autologous synoviocytes, in the AIA model, and by MRI. The link between fibrin and calcification was examined in human RA cartilage stained for calcific deposits and in vitro in fibrinogen-stimulated chondrocytes.Results:Fibrin deposition on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA wildtype (WT) mice, while fibrinogen deficient (Fg-/-) mice were protected. Accordingly, fibrin upregulated catabolic enzymes (Adamts5 and Mmp13) in chondrocytes. Secondly, CSA was present in fibrin-rich and damaged cartilage in AIA WT but not in Fg-/- mice. In line, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-positive degraded areas. Gadolinium-enhanced MRI of human joints showed contrast-enhancement along cartilage surface in RA patients but not in controls. Finally, fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization inducing pro-calcification genes (Anx5, Pit1, Pc1) and cytokine (IL-6). Although at a much lesser extent, we observed similar fibrin-mediated mechanisms in osteoarthritis (OA).Conclusion:Fibrin deposition directly impacts on cartilage integrity via induction of catabolism, mechanical stress, and calcification. Potentially, fibrin is a key factor of cartilage damage occurring in RA as a secondary consequence of inflammation.Disclosure of Interests:None declared

scholarly journals Total Meniscus Reconstruction Using a Polymeric Hybrid-Scaffold: Combined with 3D-Printed Biomimetic Framework and Micro-Particle

Polymers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1910
Author(s):  
Hun-Jin Jeong ◽  
Se-Won Lee ◽  
Myoung Wha Hong ◽  
Young Yul Kim ◽  
Kyoung Duck Seo ◽  
...  
Keyword(s):  
Shape Matching ◽  
Femoral Condyle ◽  
Immunohistochemical Analysis ◽  
Cartilage Degeneration ◽  
Patient Specific ◽  
Hybrid Scaffold ◽  
Meniscus Tissue ◽  
Cell Source ◽  
3D Printed ◽  
Meniscus Regeneration

The meniscus has poor intrinsic regenerative capability, and its injury inevitably leads to articular cartilage degeneration. Although there are commercialized off-the-shelf alternatives to achieve total meniscus regeneration, each has its own shortcomings such as individualized size matching issues and inappropriate mechanical properties. We manufactured a polycaprolactone-based patient-specific designed framework via a Computed Tomography scan images and 3D-printing technique. Then, we completed the hybrid-scaffold by combining the 3D-printed framework and mixture micro-size composite which consists of polycaprolactone and sodium chloride to create a cell-friendly microenvironment. Based on this hybrid-scaffold with an autograft cell source (fibrochondrocyte), we assessed mechanical and histological results using the rabbit total meniscectomy model. At postoperative 12-week, hybrid-scaffold achieved neo-meniscus tissue formation, and its shape was maintained without rupture or break away from the knee joint. Histological and immunohistochemical analysis results showed obvious ingrowth of the fibroblast-like cells and chondrocyte cells as well as mature lacunae that were embedded in the extracellular matrix. Hybrid-scaffolding resulted in superior shape matching as compared to original meniscus tissue. Histological analysis showed evidence of extensive neo-meniscus cell ingrowth. Additionally, the hybrid-scaffold did not induce osteoarthritis on the femoral condyle surface. The 3D-printed hybrid-scaffold may provide a promising approach that can be applied to those who received total meniscal resection, using patient-specific design and autogenous cell source.

scholarly journals IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Cartilage ◽  
2021 ◽  
pp. 194760352110267
Author(s):  
E.M. van Helvoort ◽  
H.M. de Visser ◽  
F.P.J.G. Lafeber ◽  
K. Coeleveld ◽  
S. Versteeg ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Single Molecule ◽  
Mechanical Allodynia ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Synovial Inflammation ◽  
Interleukin 4 ◽  
Analgesic Effects ◽  
Metabolic Dysregulation ◽  
Anti Inflammatory

Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

scholarly journals Exosomes derived from miR-126-3p-overexpressing synovial fibroblasts suppress chondrocyte inflammation and cartilage degradation in a rat model of osteoarthritis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan Zhou ◽  
Jianghua Ming ◽  
Yaming Li ◽  
Bochun Li ◽  
Ming Deng ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Apoptotic Cell ◽  
Synovial Fibroblasts ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Exosomal Mirnas ◽  
Exosomal Mirna ◽  
And Control ◽  
And Cartilage

AbstractMicroRNAs (miRNAs) encapsulated within exosomes can serve as essential regulators of intercellular communication and represent promising biomarkers of several aging-associated disorders. However, the relationship between exosomal miRNAs and osteoarthritis (OA)-related chondrocytes and synovial fibroblasts (SFCs) remain to be clarified. Herein, we profiled synovial fluid-derived exosomal miRNAs and explored the effects of exosomal miRNAs derived from SFCs on chondrocyte inflammation, proliferation, and survival, and further assessed their impact on cartilage degeneration in a surgically-induced rat OA model. We identified 19 miRNAs within synovial fluid-derived exosomes that were differentially expressed when comparing OA and control patients. We then employed a microarray-based approach to confirm that exosomal miRNA-126-3p expression was significantly reduced in OA patient-derived synovial fluid exosomes. At a functional level, miRNA-126-3p mimic treatment was sufficient to promote rat chondrocyte migration and proliferation while also suppressing apoptosis and IL-1β, IL-6, and TNF-α expression. SFC-miRNA-126-3p-Exos were able to suppress apoptotic cell death and associated inflammation in chondrocytes. Our in vivo results revealed that rat SFC-derived exosomal miRNA-126-3p was sufficient to suppress the formation of osteophytes, prevent cartilage degeneration, and exert anti-apoptotic and anti-inflammatory effects on articular cartilage. Overall, our findings indicate that SFC exosome‐delivered miRNA-126-3p can constrain chondrocyte inflammation and cartilage degeneration. As such, SFC-miRNA-126-3p-Exos may be of therapeutic value for the treatment of patients suffering from OA.

Maltol inhibits the progression of osteoarthritis via the nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 signal pathway in vitro and in vivo

2021 ◽  
Author(s):  
Ding-Chao Zhu ◽  
Yi-Han Wang ◽  
Jia-Hao Lin ◽  
Zhi-Min Miao ◽  
Jia-Jing Xu ◽  
...  
Keyword(s):  
Cartilage Degeneration ◽  
Degenerative Joint Disease ◽  
Signal Pathway ◽  
Joint Disease ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Articular Cartilage Degeneration

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration and inflammation. Currently, there is hardly any effective treatment for OA due to its complicated pathology and...

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