scholarly journals Intracellular versus extracellular inhibition of calpain I causes differential effects on pain in a rat model of joint inflammation

2021 ◽  
Vol 17 ◽  
pp. 174480692110161
Author(s):  
Jason J McDougall ◽  
Miranda McConnell ◽  
Allison R Reid
Keyword(s):  
Joint Pain ◽  
Acute Inflammation ◽  
Weight Bearing ◽  
Joint Inflammation ◽  
Local Administration ◽  
Calpain Inhibitor ◽  
Mast Cell Tryptase ◽  
Calcium Dependent ◽  
Protease Activated Receptor 2 ◽  
Arthritic Joints

Calpain I is a calcium-dependent cysteine protease which has dual effects on tissue inflammation depending on its cellular location. Intracellularly, calpain I has pro-inflammatory properties but becomes anti-inflammatory when exteriorised into the extracellular space. In this study, the effect of calpain I on joint pain was investigated using the kaolin/carrageenan model of acute synovitis. Evoked pain behaviour was determined by von Frey hair algesiometry and non-evoked pain was measured using dynamic hindlimb weight bearing. Local administration of calpain I reduced secondary allodynia in the acute inflammation model and this effect was blocked by the cell impermeable calpain inhibitor E-64c. Calpain I also blocked the algesic effect of the protease activated receptor-2 (PAR-2) cleaving enzyme mast cell tryptase. The cell permeable calpain blocker E-64d also produced analgesia in arthritic joints. These data suggest that calpain I produces disparate effects on joint pain viz. analgesia when present extracellularly by disarming PAR-2, and pro-algesic when the enzyme is inside the cell.

scholarly journals Research Progress on Acupuncture Treatment of Knee Osteoarthritis

2021 ◽  
Vol 9 (4) ◽  
pp. 106-110
Author(s):  
Zhang Yueyu ◽  
Song Aiqun ◽  
Peng Ying
Keyword(s):  
Acupuncture Therapy ◽  
Knee Joint ◽  
Knee Osteoarthritis ◽  
Joint Pain ◽  
Acupuncture Treatment ◽  
Treatment Plan ◽  
Joint Inflammation ◽  
Research Progress ◽  
Osteoarthritis Of The Knee ◽  
Joint Function

Osteoarthritis of the knee is a common clinical degenerative disease, which occurs in middle-aged and elderly people. Acupuncture therapy has a significant effect in the treatment of knee osteoarthritis, and is gradually accepted by more and more patients. Observing the treatment of knee osteoarthritis by different acupuncture and moxibustion therapies, we can find that acupuncture treatment of knee osteoarthritis has the advantages of relieving knee joint pain, improving knee joint function, absorbing knee joint inflammation, and promoting the recovery of damaged soft tissue. The treatment of osteoarthritis provides a more effective treatment plan.

Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis

2007 ◽  
Vol 26 (8) ◽  
pp. 1284-1292 ◽  
Author(s):  
Shunji Nakano ◽  
Takuya Mishiro ◽  
Shigeyuki Takahara ◽  
Hiromichi Yokoi ◽  
Daisuke Hamada ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mast Cell ◽  
Mast Cell Tryptase ◽  
Protease Activated Receptor 2

scholarly journals The Receptor for Parathyroid Hormone and Parathyroid Hormone-Related Peptide Is Hydrolyzed and Its Signaling Properties Are Altered by Directly Binding the Calpain Small Subunit

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2336-2344 ◽  
Author(s):  
Masako Shimada ◽  
Matthew J. Mahon ◽  
Peter A. Greer ◽  
Gino V. Segre
Keyword(s):  
Parathyroid Hormone ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Small Subunit ◽  
Hek293 Cells ◽  
Calpain Inhibitor ◽  
Dependent Manner ◽  
Intact Cells ◽  
Calcium Dependent

Abstract We show calcium-dependent, direct binding between the N-terminal portion of the PTH/PTHrP receptor (PTH1R) C-terminal intracellular tail and the calpain small subunit. Binding requires, but may not be limited to, amino acids W474, S475, and W477. The wild-type, full-length rat (r) PTH1R, but not rPTH1R with W474A/W477A substitutions, copurifies with the endogenous calpain small subunit in HEK293 cells. Calpain hydrolyzes ΔNt-rPTH1R, a receptor with a 156-amino acid N-terminal deletion, in a calcium-dependent manner in vitro and in intact cells. Most importantly, PTH stimulation increases the cleavage of ΔNt-rPTH1R and rPTH1R-yellow fluorescent protein in HEK293 cells, and of talin in HEK293 cells expressing rPTH1R-yellow fluorescent protein and in ROS17/2.8 osteoblast-like cells that express rPTH1R endogenously. The absence of calpain in Capn4-null embryonic fibroblasts and the lowered calpain activity in MC3T3-E1 osteoblastic cells due to stable expression of the calpain inhibitor, calpastatin, reduce PTH-stimulated cAMP accumulation. The calpain small subunit is the second protein, in addition to the sodium-hydrogen exchanger regulatory factor, and the first enzyme that binds the PTH1R; PTH1R bound to both of these proteins results in altered PTH signaling.

Gait analysis and weight bearing in pre-clinical joint pain research

2018 ◽  
Vol 300 ◽  
pp. 92-102 ◽  
Author(s):  
Kristina Ängeby Möller ◽  
Heta Svärd ◽  
Anni Suominen ◽  
Jarmo Immonen ◽  
Johanna Holappa ◽  
...  
Keyword(s):  
Gait Analysis ◽  
Joint Pain ◽  
Weight Bearing ◽  
Pain Research

In vitro selection of Phytomonas serpens cells resistant to the calpain inhibitor MDL28170: alterations in fitness and expression of the major peptidases and efflux pumps

Parasitology ◽  
2017 ◽  
Vol 145 (3) ◽  
pp. 355-370 ◽  
Author(s):  
SIMONE S. C. OLIVEIRA ◽  
INÊS C. GONÇALVES ◽  
VITOR ENNES-VIDAL ◽  
ANGELA H. C. S. LOPES ◽  
RUBEM F. S. MENNA-BARRETO ◽  
...  
Keyword(s):  
In Vitro Selection ◽  
Oncopeltus Fasciatus ◽  
Calpain Inhibitor ◽  
Insect Vector ◽  
Peptidase Activity ◽  
Wild Type ◽  
Calcium Dependent ◽  
Calpain Inhibitors ◽  
Selection Of

SUMMARYThe species Phytomonas serpens is known to express some molecules displaying similarity to those described in trypanosomatids pathogenic to humans, such as peptidases from Trypanosoma cruzi (cruzipain) and Leishmania spp. (gp63). In this work, a population of P. serpens resistant to the calpain inhibitor MDL28170 at 70 µm (MDLR population) was selected by culturing promastigotes in increasing concentrations of the drug. The only relevant ultrastructural difference between wild-type (WT) and MDLR promastigotes was the presence of microvesicles within the flagellar pocket of the latter. MDLR population also showed an increased reactivity to anti-cruzipain antibody as well as a higher papain-like proteolytic activity, while the expression of calpain-like molecules cross-reactive to anti-Dm-calpain (from Drosophila melanogaster) antibody and calcium-dependent cysteine peptidase activity were decreased. Gp63-like molecules also presented a diminished expression in MDLR population, which is probably correlated to the reduction in the parasite adhesion to the salivary glands of the insect vector Oncopeltus fasciatus. A lower accumulation of Rhodamine 123 was detected in MDLR cells when compared with the WT population, a phenotype that was reversed when MDLR cells were treated with cyclosporin A and verapamil. Collectively, our results may help in the understanding of the roles of calpain inhibitors in trypanosomatids.

scholarly journals NLRP3- and AIM2-autonomy in a mouse model of MSU crystal-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1[beta] expression as relevant therapy for gout patients.

2019 ◽  
Author(s):  
Alexandre Mariotte ◽  
Aurore Decauwer ◽  
Chrystelle Po ◽  
Cherine Abou-Faycal ◽  
Angelique Pichot ◽  
...  
Keyword(s):  
Mouse Model ◽  
Acute Inflammation ◽  
Joint Inflammation ◽  
Inflammatory Action ◽  
Recognition Receptor ◽  
Msu Crystals

The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1b in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1b; secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Here, we provide an extensive clinical, biological and molecular characterization of the acute uratic inflammation mouse model induced by subcutaneous injection of MSU crystals, which accurately mimics human gout. Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities, among which the use of topical application of imiquimod to promote interferon-dependent anti-inflammatory action maybe relevant.

scholarly journals Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-α antibody in a murine model of rheumatoid arthritis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Kiyomitsu Katsumata ◽  
Jun Ishihara ◽  
Kazuto Fukunaga ◽  
Ako Ishihara ◽  
Eiji Yuba ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Injection Site ◽  
Therapeutic Efficacy ◽  
Local Administration ◽  
Systemic Injection ◽  
Binding Peptide ◽  
Ecm Proteins ◽  
Peptide Conjugation ◽  
Arthritic Joints

Abstract Background Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model. Methods α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated α-TNF (PlGF-2123-144-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse. Results PlGF-2123-144 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose. Conclusion These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

scholarly journals Reducing the Volume of Low-Value Outpatient MRI Joint Examinations in Patients ≥55 Years of Age

2020 ◽  
Vol 71 (1) ◽  
pp. 83-91
Author(s):  
Joshua W. Kandiah ◽  
Vivian W. Y. Chan ◽  
Jing Luo ◽  
Flora Dong ◽  
James P. Nugent ◽  
...  
Keyword(s):  
Digital Media ◽  
Joint Pain ◽  
Weight Bearing ◽  
X Rays ◽  
Red Flags ◽  
Urban Hospital ◽  
X Ray Imaging ◽  
Shoulder Mri ◽  
Picture Archiving And Communication ◽  
Magnetic Resonance Imaging Mri

Purpose: Magnetic resonance imaging (MRI) is not beneficial in patients with joint pain and concomitant osteoarthritis (OA). We attempt to determine whether evaluation of OA via X-rays can reduce inappropriate MRI and computed tomography (CT) arthrogram use. In our jurisdiction, CT arthrograms are used as surrogate tests because of MRI wait times. Materials and Methods: Our intervention required patients ≥55 years of age scheduled for outpatient MRI of the knee/hip/shoulder at an urban hospital to have X-rays (weight bearing when appropriate) from within 1 year. Red flags (ie, neoplasm, infection) were identified for which MRI would be indicated regardless. Through review of radiographs on picture archiving and communication system/digital media and use of the validated Kellgren-Lawrence (KL) OA scale, radiologists assessed the presence and degree of OA. A finding of significant OA (KL > 2) without red flags would preclude MRI. Monthly averages of MRI and CT arthrogram examinations were measured 33 months before and 23 months following introduction of the intervention. Results: The proportion of protocoled MRI requisitions that were avoided was 21%. If extrapolated to the province of British Columbia, 2419 of 11 700 examinations could have been prevented in the past year. The average monthly number of knee/hip/shoulder MRI examinations as a percentage of total MRI examinations decreased from 4.9% to 4.3% ( P < .02) following the intervention. The average monthly number of knee/hip/shoulder CT arthrogram examinations decreased from 20.6 to 12.1 ( P < .0001). Conclusion: We were able to decrease the number of MRI and CT arthrogram examinations in patients ≥55 years of age with joint pain by implementing an evaluation for OA via recent X-ray imaging.

Sign in / Sign up

Export Citation Format

Share Document