Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

Song, Jaeyong; Hwang, Inyong; Cho, Kyung H.; Garcia, Michael A.; Kim, Arthur J.; Wang, Tiffany H.; Lindström, Tamsin M.; Lee, Annette T.; Nishimura, Toshihiko; Zhao, Lei; Morser, John; Nesheim, Michael E.; Goodman, Stuart B.; Lee, David M.; Bridges, S. Louis; Gregersen, Peter K.; Leung, Lawrence L.K.; Robinson, William H.

doi:10.1172/jci46387

Cited by 50 publications

(56 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This hypothesis is in agreement with the data from the HUS model, in which deficiency of CPB2 has a greater effect than deficiency of CPN [52]. In humans, the importance of CPB2 in regulating C5a is shown by the association of the longacting CPB2 form with a reduced risk of developing severe rheumatoid arthritis [12].…”

Section: Different Roles Of Cpb2 and Cpnsupporting

confidence: 90%

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Leung

Morser

2018

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Two basic carboxypeptidases, carboxypeptidase B2 (CPB2) and carboxypeptidase N (CPN) are present in plasma. CPN is constitutively active, whereas CPB2 circulates as a precursor, procarboxypeptidase B2 (proCPB2), that needs to be activated by the thrombin-thrombomodulin complex or plasmin bound to glycosaminoglycans. The substrate specificities of CPB2 and CPN are similar; they both remove C-terminal basic amino acids from bioactive peptides and proteins, thereby inactivating them. The complement cascade is a cascade of proteases and cofactors activated by pathogens or dead cells, divided into two phases, with the second phase only being triggered if sufficient C3b is present. Complement activation generates anaphylatoxins: C3a, which stimulates macrophages; and C5a, which is an activator and attractant for neutrophils. Pharmacological intervention with inhibitors has shown that CPB2 delays fibrinolysis, whereas CPN is responsible for systemic inactivation of C3a and C5a. Among mice genetically deficient in either CPB2 or CPN, in a model of hemolytic-uremic syndrome, Cpb2 mice had the worst disease, followed by Cpn mice, with wild-type (WT) mice being the most protected. This model is driven by C5a, and shows that CPB2 is important in inactivating C5a. In contrast, when mice were challenged acutely with cobra venom factor, the reverse phenotype was observed; Cpn mice had markedly worse disease than Cpb2 mice, and WT mice were resistant. These observations need to be confirmed in humans. Therefore, CPB2 and CPN have different roles. CPN inactivates C3a and C5a generated spontaneously, whereas proCPB2 is activated at specific sites, where it inactivates bioactive peptides that would overwhelm CPN.

show abstract

Section: Different Roles Of Cpb2 and Cpnsupporting

confidence: 90%

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Leung

Morser

2018

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…104 In animal studies, synovial inflammation and arthritis were significantly increased in TAFI (−/−) mice subjected to experimental RA due to decreased TAFI-dependent inactivation of C5a. 108 TAFI’s important role in modulating inflammatory joint disease in humans is further supported by the fact that TAFI is expressed in synovium and in synovial fluid, 90 and that patients with RA with the enzymatically more stable TAFI polymorphism (rs1926447, Thr325Ile) are better protected against joint disease. 108 The extent to which TAFI may provide an important molecular link between joint inflammation, joint degeneration and hemostasis in HA is interesting and remains to be studied.…”

Section: The Pathobiology Of Hemophilic Arthropathymentioning

confidence: 99%

Advances and challenges in hemophilic arthropathy

Wyseure

Mosnier

Drygalski

2016

Seminars in Hematology

106

View full text Add to dashboard Cite

Hemophilic arthropathy is a form of joint disease that develops in secondary to joint bleeding and presents with synovial hypertrophy, cartilage and bony destruction. The arthropathy can develop despite clotting factor replacement and is especially disabling in the aging population. Pathobiological tissue changes are triggered by release of hemoglobin and iron deposition in the joint, but the sequence of events and the molecular mechanisms resulting in joint deterioration are incompletely understood. Treatment options other than clotting factor replacement are limited. Improvements in the treatment of hemophilia necessitate a better understanding of the processes that lead to this disabling condition and better diagnostic tools. Towards that end, studies of the molecular mechanisms leading to the arthropathy, as well as the development of sensitive imaging techniques and biomarkers are needed. These will pave the way to identify the cause of acute pain such as joint bleeding or synovitis, detect early, potentially reversible structural changes, and predict progression of disease. This review describes current imaging techniques and the development of high resolution musculoskeletal ultrasound with power Doppler to afford point-of-care diagnosis and management, the potential utility of diagnostic biomarkers, and summarizes our current knowledge of the pathobiology of hemophilic arthropathy.

show abstract

“…Therefore, the struggle between resolving and perpetuating factors also involves clotting and fibrinolysis inside joints, and this battle is completely skewed towards fibrin deposition in rheumatoid hosts [8][9][10][11][12][13]. We can positively regard rheumatoid arthritis as an extravascular thrombophilia.…”

Section: Fibrin Deposition and The Sequence From Early To Establishedmentioning

confidence: 99%

“…This post-translational modification usually leads to functional alterations of the substrates, and has been found to hamper antithrombin enzymatic activity, as well as the digestion of fibrin [12]. Also the degrading rate of carboxypeptidase B (CPB) has been found decreased in rheumatoid joints [13].…”

Section: Fibrin Deposition and The Sequence From Early To Establishedmentioning

confidence: 99%

Targets Hidden by Fibrin Networks Still Need to Find Their Place in the Armamentarium for Rheumatoid Arthritis

Gabucio¹,

Sánchez‐Pernaute²

2016

HealthCare Current Reviews

View full text Add to dashboard Cite

HCCR, an open access journal Page 3 of 4 modification of peptides facilitates their recognition as auto antigens [32]. Moreover, the development of antibodies to citrullinated peptides is relatively restricted to the disease. Citrullination is carried out by the family of peptidyl deiminases (PAD), out of which PAD2 emerges as an attractive therapeutic target. Of all isoforms, PAD2 shows the higher affinity for fibrin domains in vitro, and it has been found to be enriched in the synovial fluid of patients with rheumatoid arthritis and spondyloarthritis, as compared to osteoarthritis [33,34]. An increase in PAD has been put in relationship with erosive disease, and the presence of anti citrullinated antibodies is currently considered a marker of severe disease [35]. Altogether, this suggests that particular subgroups of patients would benefit from the inhibition of PAD2 activity. Limitations to the Development of Fibrin-Based TherapiesTwo major criticisms have hindered the progression of fibrin research in rheumatoid arthritis. The first one derived from the extrapolation of histopathological findings in synovial tissues from end-stage disease. Fibrin was for a long time considered a bystander product of inflammation. This hurdle was overcome with the studies performed in experimental models, and more recently, when fibrin was shown to be a major auto antigen of the disease. The second point raised was the lack of specificity of intra-articular fibrin deposition. This drawback is shared by most studies approaching the invasive phenotype of rheumatoid synovial fibroblasts, which have failed to show intrinsic alterations. In concordance, our group has found a similar profile of gene induction in fibroblasts from osteoarthritic joints to the one depicted by rheumatoid fibroblasts upon exposure to fibrin (unpublished data). This rather supports that fibrin networks provide a micro environmental imprinting, as responsible for the aggressive features of these cells. Besides, we did observe differences in the magnitude of the cell response between both conditions, probably due to the higher expression level of TLR4 in rheumatoid as compared to osteoarthritic synovial fibroblasts, as has been observed [25,26].In conclusion, complexity of rheumatoid arthritis warrants a multi-target approach in order to shut down mechanisms involved in disease progression. In the next future, a better characterization of each phenotype will facilitate the use of tailored strategies, in which a place for fibrin-based therapies can be forecasted. AcknowledgementThe authors' work was supported by the Conchita Rabago Foundation.

show abstract

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

Cited by 50 publications

References 57 publications

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Advances and challenges in hemophilic arthropathy

Targets Hidden by Fibrin Networks Still Need to Find Their Place in the Armamentarium for Rheumatoid Arthritis

Contact Info

Product

Resources

About