scholarly journals Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

2014 ◽  
Vol 57 (22) ◽  
pp. 9598-9611 ◽  
Author(s):  
Timothy P. Spicer ◽  
Jianwen Jiang ◽  
Alexander B. Taylor ◽  
Jun Yong Choi ◽  
P. John Hart ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Matrix Metalloproteinase ◽  
Cartilage Degradation ◽  
Matrix Metalloproteinase 13 ◽  
Binding Inhibitors

scholarly journals Galectin network in osteoarthritis: galectin-4 programs a pathogenic signature of gene and effector expression in human chondrocytes in vitro

2021 ◽  
Author(s):  
Katharina M. Pichler ◽  
Anita Fischer ◽  
Jürgen Alphonsus ◽  
Catharina Chiari ◽  
Sebastian Schmidt ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Cartilage Degradation ◽  
Cross Linking ◽  
Transcriptome Data ◽  
Matrix Metalloproteinase 13 ◽  
Carbohydrate Recognition Domains ◽  
Inflammatory Proteins ◽  
Oa Chondrocytes

AbstractGalectin-4 (Gal-4) is a member of the galectin family, which have been identified as galactose-binding proteins. Gal-4 possesses two tandem repeat carbohydrate recognition domains and acts as a cross-linking bridge in sulfatide-dependent glycoprotein routing. We herein document its upregulation in osteoarthritis (OA) in correlation with the extent of cartilage degradation in vivo. Primary human OA chondrocytes in vitro respond to carbohydrate-inhibitable Gal-4 binding with the upregulation of pro-degradative/-inflammatory proteins such as interleukin-1β (IL-1β) and matrix metalloproteinase-13 (MMP-13), as documented by RT-qPCR-based mRNA profiling and transcriptome data processing. Activation of p65 by phosphorylation of Ser536 within the NF-κB pathway and the effect of three p65 inhibitors on Gal-4 activity support downstream involvement of such signaling. In 3D (pellet) cultures, Gal-4 presence causes morphological and biochemical signs of degradation. Taken together, our findings strongly support the concept of galectins acting as a network in OA pathogenesis and suggest that blocking their activity in disease progression may become clinically relevant in the future.

scholarly journals Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

2016 ◽  
Vol 113 (19) ◽  
pp. 5453-5458 ◽  
Author(s):  
Wafa Bouaziz ◽  
Johanna Sigaux ◽  
Dominique Modrowski ◽  
Claire-Sophie Devignes ◽  
Thomas Funck-Brentano ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Matrix Metalloproteinase ◽  
Wnt Signaling ◽  
Cartilage Degradation ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Matrix Metalloproteinase 13 ◽  
The Impact ◽  
Mmp13 Expression

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/β-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (∆Hif1αchon) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1α lowered transcription factor 4 (TCF4)–β-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1α interacting with β-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, ΔHif1αchon mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4–β-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1α–β-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1α in OA and highlights the HIF1α–β-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.

scholarly journals Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis

2021 ◽  
Vol 22 (4) ◽  
pp. 1742
Author(s):  
Qichan Hu ◽  
Melanie Ecker
Keyword(s):  
Articular Cartilage ◽  
Matrix Metalloproteinase ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Type Ii Collagen ◽  
Cartilage Degradation ◽  
Type Ii ◽  
Inhibitor Development ◽  
Matrix Metalloproteinase 13 ◽  
Promising Target

Osteoarthritis (OA) is a common degenerative disease characterized by the destruction of articular cartilage and chronic inflammation of surrounding tissues. Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type II collagen. Hence, it is an attractive target for the treatment of OA. However, the detailed molecular mechanisms of OA initiation and progression remain elusive, and, currently, there are no interventions available to restore degraded cartilage. This review fully illustrates the involvement of MMP-13 in the initiation and progression of OA through the regulation of MMP-13 activity at the molecular and epigenetic levels, as well as the strategies that have been employed against MMP-13. The aim of this review is to identify MMP-13 as an attractive target for inhibitor development in the treatment of OA.

Differential Regulation of Articular Cartilage Biomechanical and Biochemical Properties by IGF-1 and TGF-β1 During In Vitro Growth

2009 ◽  
Author(s):  
Michael E. Stender ◽  
Christian R. Flores ◽  
Kristin J. Dills ◽  
Gregory M. Williams ◽  
Kevin M. Stewart ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Growth Models ◽  
Biochemical Properties ◽  
Low Friction ◽  
Cartilage Growth ◽  
Detailed Characterization ◽  
Naturally Occurring ◽  
Tgf Β1

Articular cartilage (AC) is a load bearing material that provides a low friction wear resistant interface in synovial joints. Naturally-occurring and stimulated intrinsic repair of damaged AC is ineffective. Thus, there is a desire to engineer effective replacement tissue that could be used for AC repair. Previous studies [1] have shown that culture of immature cartilage with medium including TGF-β1 will result in a more mature tissue than culture with IGF-1. Detailed characterization of tissue mechanical properties would be helpful for development of cartilage growth models [2].

scholarly journals Characterization of an exosite binding inhibitor of matrix metalloproteinase 13

2007 ◽  
Vol 17 (1) ◽  
pp. 66-71 ◽  
Author(s):  
L. T. Gooljarsingh ◽  
A. Lakdawala ◽  
F. Coppo ◽  
L. Luo ◽  
G. B. Fields ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 13

Finite Element Modelling of In Vitro Articular Cartilage Wear in the Patellofemoral Joint

2012 ◽  
Author(s):  
Lingmin Li ◽  
Shantanu Patil ◽  
Nick Steklov ◽  
Won Bae ◽  
Darryl D. D’Lima ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cruciate Ligament ◽  
Computational Simulation ◽  
Knee Kinematics ◽  
Cartilage Degradation ◽  
Knee Oa ◽  
Cartilage Wear ◽  
Anterior Cruciate ◽  
A Site

The mechanism by which altered knee joint motions and loads (e.g., following anterior cruciate ligament (ACL) injury) contribute to the development of knee osteoarthritis (OA) is not well understood. One mechanobiological hypothesis is that articular cartilage degradation is initiated when altered knee kinematics increase loading on certain regions of the articular surfaces and decrease loading on other regions [1]. If homeostatic loading conditions vary from region to region, then load changes induced by altered kinematics could initiate cartilage degradation in a site-specific manner. This hypothesis is attractive from a computational simulation perspective since it is based on mechanical factors that lend themselves well to physical modeling. If computational simulations could predict the knee OA development process, then they could potentially be used to facilitate the design of new or improved treatments for the disease.

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