scholarly journals A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2705
Author(s):  
Tomasz Janczi ◽  
Florian Meier ◽  
Yuliya Fehrl ◽  
Raimund W. Kinne ◽  
Beate Böhm ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Transient Receptor Potential ◽  
Joint Destruction ◽  
Receptor Potential ◽  
Synovial Fibroblasts ◽  
Sirtuin 1 ◽  
Metabolic Energy ◽  
Transient Receptor Potential Vanilloid ◽  
Pannexin 1 ◽  
Transient Receptor

Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.

scholarly journals Transient Receptor Potential Vanilloid 5 Mediates Ca2+ Influx and Inhibits Chondrocyte Autophagy in a Rat Osteoarthritis Model

2017 ◽  
Vol 42 (1) ◽  
pp. 319-332 ◽  
Author(s):  
Yingliang Wei ◽  
Yanfang Wang ◽  
Yutong Wang ◽  
Lunhao Bai
Keyword(s):  
Articular Cartilage ◽  
Transient Receptor Potential ◽  
Joint Destruction ◽  
Receptor Potential ◽  
B Cell Lymphoma ◽  
Transient Receptor Potential Channel ◽  
Ruthenium Red ◽  
Protective Mechanism ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

Background: Autophagy, a self-protective mechanism of chondrocytes, has become a promising target to impede the progress of osteoarthritis (OA). Autophagy is regulated by cytosolic Ca2+ activity and may thus be modified by the Ca2+ permeable transient receptor potential channel vanilloid 5 (TRPV5). Therefore, we investigated the potential role of TRPV5 in mediating Ca2+ influx and in inhibiting chondrocyte autophagy in a rat OA model. Methods: The rat OA model was assessed by macroscopic and histological analyses. light chain 3B (LC3B) immunolocalization was detected by immunohistochemistry. TRPV5, LC3B and calmodulin in OA articular cartilage were assessed by real time polymerase chain reaction (RT-PCR) and western blotting. TRPV5 small interfering RNA (TRPV5 siRNA) were transfected into rat primary chondrocyte then the calmodulin and LC3B was detected by immunofluorescence. The functionality of the TRPV5 was assessed by Ca2+ influx. Western blot was used to measure autophagy-related proteins. Results: We constructed a monosodium iodoacetate (MIA) -induced rat OA model and found that ruthenium red (TRPV5 inhibitor) slowed the progression of joint destruction. We found that the TRPV5 and calmodulin were up-regulated but LC3B was down-regulated in articular cartilage following prolonged progression of OA. Furthermore, the up-regulated TRPV5 channel caused an increase in the Ca2+ influx in chondrocytes. The up-regulation of TRPV5 stimulated Ca2+ influx, which inhibited autophagy by increasing the production of calmodulin, phosphorylation of calmodulin dependent protein kinases II (p-CAMK II), phosphorylation of Beclin1 (p-Beclin1), and protein of B-cell lymphoma-2 (Bcl-2), and attenuating ratio of LC3-II/ LC3-. Conclusion: Up-regulated TRPV5 as an initiating factor inhibited chondrocyte autophagy via the mediation of Ca2+ influx.

Abstract 419: Metabocin TM Increases Lipolytic Pathways to Counter High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Baskaran Thyagarajan ◽  
Sara Cisneros ◽  
Ross Cook ◽  
Padmamalini Baskaran
Keyword(s):  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Sirtuin 1 ◽  
Transient Receptor Potential Vanilloid ◽  
High Fat ◽  
Ppar Alpha ◽  
Alcoholic Fatty Liver ◽  
Transient Receptor ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFDLD) is a comorbidity of high fat diet-induced obesity. NAFLD leads to steatohepatitis and hepatic steatosis, which progress into cirrhosis and liver cancer. Currently, there is no single strategy to counter NAFLD. In our effort to understand the role of transient receptor potential vanilloid receptor in the pathophysiology of high fat diet-induced, non-alcoholic fatty liver disease, we discovered that mammalian liver expresses transient receptor potential vanilloid 1 protein and that Metabocin TM {( E )- N -[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide; also know as capsaicin; an agonist of transient receptor potential vanilloid 1 channel protein} significantly prevented mice from diet-induced NAFLD. Feeding high fat diet (60% calories from fat) for 32 weeks, from the age of 6 weeks until 38 weeks, caused hypertension, hyperglycemia, glucose intolerance and hyper triglyceridemia in the wild type mice and Metabocin TM prevented these effects. Metabocin TM markedly prevented hepatic steatosis and decreased lipid accumulation in the liver. Also, Metabocin TM significantly increased the expression of lipolytic PPAR alpha, PPAR gamma co activator 1 alpha, sirtuin-1 and forkhead box protein 01, while suppressed the expression of lipogenic stearoyl CoA desaturase 1. Further, Metabocin TM increased liver lipolysis, facilitated the activation of sirtuin-1 via Ca 2+ /Calmodulin dependent protein kinase II/AMPK-dependent mechanism and induced an interaction between sirtuin-1 and PPAR alpha. Metabocin TM also increased the expression of lipin-1 (a transcriptional regulator of PPAR alpha) and mitochondrial UCP-1. Our data provide evidence for the emergence of Metabocin TM as a novel drug molecule to antagonize NAFLD and its associated pathologies.

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