scholarly journals Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation

2001 ◽  
Vol 194 (2) ◽  
pp. 189-204 ◽  
Author(s):  
Matthias Ernst ◽  
Melissa Inglese ◽  
Paul Waring ◽  
Ian K. Campbell ◽  
Shisan Bao ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Joint Pathology ◽  
Stat Signaling ◽  
Chronic Synovitis ◽  
Src Homology 2 Domain ◽  
Gastrointestinal Ulceration

The receptor subunit gp130 transduces multiple cell type–specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ΔSTAT “knock-in” mutation which deleted all STAT-binding sites. gp130ΔSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ΔSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ΔSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.

Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase

2019 ◽  
Vol 21 (24) ◽  
pp. 12905-12915 ◽  
Author(s):  
Yaru Wei ◽  
Zhiyang Zhang ◽  
Nai She ◽  
Xin Chen ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Negative Feedback ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Jak Kinase ◽  
Stat Signaling ◽  
Suppressors Of Cytokine Signaling ◽  
Insight Into

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK–STAT) signaling pathway by inhibiting the activity of JAK kinase.

scholarly journals Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 867-880 ◽  
Author(s):  
Rula A. Abbud ◽  
Robert Kelleher ◽  
Shlomo Melmed
Keyword(s):  
Transcription Factors ◽  
Leukemia Inhibitory Factor ◽  
Expression Profiles ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Induced Expression ◽  
Transcription 3

Abstract Leukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke’s cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH3) cells. In addition to genes known to respond to LIF in corticotrope cells [e.g. suppressor of cytokine signaling-3 (SOCS-3), signal transducer and activator of transcription-3, SH2 domain-containing tyrosine phosphatase-1, and proopiomelanocortin (POMC)], corticotrope-specific changes were also observed for genes involved in glycolysis and gluconeogenesis, transcription factors, signaling molecules, and expressed sequence tags. Two transcription factors identified, CCAAT/enhancer-binding protein β (C/EBPβ) and glial cell-derived neurotrophic factor (GDNF)-inducible factor (GIF), dose-dependently induced expression of the rat POMC promoter when overexpressed in AtT-20 cells. LIF further induced POMC transcription with C/EBPβ, but not with GIF. C/EBPβ also induced expression of the SOCS-3 promoter that was further enhanced by cotreatment with LIF. However, GIF did not affect SOCS-3 expression. These results indicate that C/EBPβ and GIF are downstream effectors of LIF corticotrope action. LIF also stimulates the expression of inhibitors of its actions, such as SOCS-3 and SH2 domain-containing tyrosine phosphatase-1. α2-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFβ/bone morphogenic protein signaling, was induced by LIF in a signal transducer and activator of transcription-3-dependent fashion. Pretreatment with AHSG/fetuin blocked LIF-induced expression of the POMC promoter independently of SOCS-3. Thus, using GeneChips, C/EBPβ and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.

scholarly journals ORF3a Protein of Severe Acute Respiratory Syndrome Coronavirus 2 Inhibits Interferon-Activated Janus Kinase/Signal Transducer and Activator of Transcription Signaling via Elevating Suppressor of Cytokine Signaling 1

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Wang ◽  
Xiaofeng Yang ◽  
Mingke Chang ◽  
Ziyang Xue ◽  
Weirong Wang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Proteasomal Degradation ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Signal Transducer ◽  
Global Public Health ◽  
Suppressor Of Cytokine Signaling ◽  
Stat Signaling

Coronavirus disease 2019 (COVID-19) has caused a crisis to global public health since its outbreak at the end of 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of COVID-19, appears to efficiently evade the host immune responses, including interferon (IFN) signaling. Several SARS-CoV-2 viral proteins are believed to involve in the inhibition of IFN signaling. In this study, we discovered that ORF3a, an accessory protein of SARS-CoV-2, inhibited IFN-activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling via upregulating suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling. ORF3a induced SOCS1 elevation in a dose- and time-dependent manner. RNAi-mediated silencing of SOCS1 efficiently abolished ORF3a-induced blockage of JAK/STAT signaling. Interestingly, we found that ORF3a also promoted the ubiquitin-proteasomal degradation of Janus kinase 2 (JAK2), an important kinase in IFN signaling. Silencing of SOCS1 by siRNA distinctly blocked ORF3a-induced JAK2 ubiquitination and degradation. These results demonstrate that ORF3a dampens IFN signaling via upregulating SOCS1, which suppressed STAT1 phosphorylation and accelerated JAK2 ubiquitin-proteasomal degradation. Furthermore, analysis of ORF3a deletion constructs showed that the middle domain of ORF3a (amino acids 70–130) was responsible for SOCS1 upregulation. These findings contribute to our understanding of the mechanism of SARS-CoV-2 antagonizing host antiviral response.

Apportionment of Impairment from Meniscal Tears and Knee Arthritis

2013 ◽  
Vol 18 (5) ◽  
pp. 1-10 ◽  
Author(s):  
Charles N. Brooks ◽  
James B. Talmage
Keyword(s):  
Medial Meniscus ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Detailed Knowledge ◽  
Meniscal Tears ◽  
Knee Arthritis ◽  
Degenerative Arthritis ◽  
Study Results ◽  
Physical Findings ◽  
Causation Analysis

Abstract Meniscal tears and osteoarthritis (osteoarthrosis, degenerative arthritis, or degenerative joint disease) are two of the most common conditions involving the knee. This article includes definitions of apportionment and causes; presents a case report of initial and recurrent tears of the medial meniscus plus osteoarthritis (OA) in the medial compartment of the knee; and addresses questions regarding apportionment. The authors, experienced impairment raters who are knowledgeable regarding the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), show that, when instructions on impairment rating are incomplete, unclear, or inconsistent, interrater reliability diminishes (different physicians may derive different impairment estimates). Accurate apportionment of impairment is a demanding task that requires detailed knowledge of causation for the conditions in question; the mechanisms of injury or extent of exposures; prior and current symptoms, functional status, physical findings, and clinical study results; and use of the appropriate edition of the AMA Guides. Sometimes the available data are incomplete, requiring the rating physician to make assumptions. However, if those assumptions are reasonable and consistent with the medical literature and facts of the case, if the causation analysis is plausible, and if the examiner follows impairment rating instructions in the AMA Guides (or at least uses a rational and hence defensible method when instructions are suboptimal), the resulting apportionment should be credible.

3. Degenerative joint disease

2000 ◽  
Vol 81 (3B) ◽  
pp. s67-s72
Author(s):  
Victoria A. Brander ◽  
Darryl L. Kaelin ◽  
Terry H. Oh ◽  
Peter A.C. Lim
Keyword(s):  
Degenerative Joint Disease ◽  
Joint Disease

Osteotomy for Correction of Premature Growth Plate Closure in 24 Dogs

1994 ◽  
Vol 07 (03) ◽  
pp. 129-135 ◽  
Author(s):  
C.W. Miller ◽  
P.W. Morgan
Keyword(s):  
Corrective Osteotomy ◽  
Functional Results ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Angular Deformity ◽  
Dynamic Correction ◽  
Age At Surgery ◽  
Limb Deformities ◽  
The Mean ◽  
A Prospective Study

SummaryTwenty-four dogs (27 limbs) were evaluated after surgery for correction of forelimb angular limb deformities. Partial ulnar ostectomies or definitive corrective osteotomies were performed depending upon the age of the dog. According to owner assessment nine of fourteen limbs were considered functionally good, or excellent, after partial ulnar ostectomies. Younger dogs appeared to have better functional results after dynamic correction with the mean age at surgery of dogs with good to excellent results being 6.5 months contrasted to the mean age at surgery of dogs with fair to poor results being 9.75 months. Ten of fourteen limbs were considered functionally good or excellent after definitive corrective osteotomy. One dog had definitive osteotomy after partial ulnar ostectomy in order to further correct a residual angular deformity. However, 58% of the limbs with radiographic follow-up had signs of degenerative joint disease (DJD). There were not significant differences between neither degree of angulation remaining after surgery and the functional result nor the degree of angulation remaining after surgery and the development of DJD. A prospective study is warranted to more objectively assess the efficacy of surgical correction of angular limb deformities in dogs.Twenty-four dogs were evaluated after surgery for correction of forelimb angular limb deformities. The results are described.

Anticoagulant Properties of Three Mucopolysaccharides Used in Rheumatology

1983 ◽  
Vol 50 (03) ◽  
pp. 652-655 ◽  
Author(s):  
F Bauer ◽  
P Schulz ◽  
G Reber ◽  
C A Bouvier
Keyword(s):  
Factor Xa ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Thrombin Time ◽  
Coagulation Tests ◽  
Amplification System ◽  
Relative Potencies ◽  
In Vivo Administration

SummaryThree mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor X a activity and the dilute thrombin time. One of the compounds, Arteparon®, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon® acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon® confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.

The Gut Microbiota of Rats under Experimental Osteoarthritis and Administration of Chondroitin Sulfate and Probiotic

2020 ◽  
Vol 82 (6) ◽  
pp. 64-73
Author(s):  
O.H. Korotkyi ◽  
◽  
T.V. Luhovska ◽  
T.M. Serhiychuk ◽  
K.O. Dvorshchenko ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Chondroitin Sulfate ◽  
Joint Inflammation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Quantitative Composition ◽  
Combined Administration ◽  
Osteoarthritis Progression ◽  
Experimental Osteoarthritis ◽  
Gut Microbiota Composition

Osteoarthritis is a most widespread chronic degenerative joint disease that causes pain, cartilage deformation, and joint inflammation. Adverse alterations of intestinal microbiota like dysbiosis may lead to metabolic syndrome and inflammation, two important components of osteoarthritis progression. Aim. In this study we investigated the effect of chondroitin sulfate and probiotics on the gut microbiome in monoiodoacetate-induced osteoarthritis model in rats. Methods. The species and quantitative composition of feces were determined using diagnostic media with selective properties. Further identification of isolated microorganisms was carried out according to morphological, tinctorial, physiological and metabolic parameters. The results are presented in the form of lg CFU/g. Results. Induction of osteoarthritis caused significant increasing the number of opportunistic enterobacteria and lactose-negative Escherichia coli against the decreasing of lacto- and bifidobacteria that may indicate a dysbiotic condition. Coadministration of chondroitin sulfate and probiotic bacteria has led to improvement the quantitative composition of the gut microbiota in experimental animals, the numerous of Bifidobacterium, Lactobacillus were increasing against decreasing the quantitative composition of opportunistic microorganisms. Conclusions. Monoiodoacetate-induced osteoarthritis caused dysbiosis of gut in rat. We observed beneficial effect of combined administration of chondroitin sulfate and probiotics on gut microbiota composition in rats with experimental osteoarthritis. Thus, adding of supplements like probiotics to standard treatment of osteoarthritis may have potentials to prevent and treat this disease.

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