Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion

Abstract

Key Points Genetic elimination of the coagulation transglutaminase fXIII limits arthritis incidence and severity in mice. FXIII supports arthritis pathogenesis through distinct mechanisms linked to joint inflammation and osteoclastogenesis.

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

“…It was suggested that the mechanism of factor XIII exacerbation of adipose inflammation and obesity sequelae was linked to fibronectin (51); however, a possible link to fibrin(ogen) was not considered. We postulate that factor XIII may be influencing HFD-induced pathologies through a mechanism whereby crosslinked fibrin drives a greater proinflammatory response and has a greater impact on ATM function than non-cross-linked fibrin, a general hypothesis supported by previous work in our laboratory (52). However, defining the precise interplay of fibrin(ogen) and factor XIII in obesity sequelae, including insulin resistance and NAFLD, remains for future investigation.…”

Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition

“…Finally, it is clear that many biologic functions of FXIII have not been thoroughly elucidated. In addition to coagulation, FXIII may have roles in arthritis(50), adipogenesis(51), and cardiac repair(52, 53). It will be important to understand the impact of FXIII inhibition on these situations before the benefit of a FXIIIa antagonist can be realized in the clinic.…”

Coagulation takes center stage in inflammation

“…Controls with FCS-containing medium, but without cytokines, indicated that FCS was not the driver of the conversion. However, Milne et al 1 could not generate Langerhans cell progeny by culture in X-Vivo medium without FCS, despite inclusion of GM-CSF, TGF-b1, and BMP7, all of which, together with TSLP, are epithelial cell-derived cytokines under physiologic conditions.…”

“…Depletion of fXIII in CIA does not reduce the numbers of T and B cells in peripheral immune organs. 1 However, it remains unknown whether fXIII-mediated, fibrin-induced activation of resident innate immune cells regulates local T-cell activation in tissues. Finally, this study, together with compelling evidence for the contribution of coagulation in rheumatoid arthritis patients, 3 not only opens new avenues for repurposing anticoagulant therapy to limit both inflammation and bone erosion but also fuels enthusiasm for the development of new drugs to selectively target components of the coagulation cascade in autoimmune diseases.…”

“…The study presents compelling evidence demonstrating that fXIII contributes to arthritis pathogenesis through distinct mechanisms linked to inflammation and destructive bone loss. 1 C omponents of the coagulation cascade originally studied for their role in hemostasis are now recognized as key players in inflammatory and autoimmune diseases. 2,3 Fibrin, the final product of the coagulation cascade, is a result of thrombin-mediated conversion of fibrinogen to an insoluble fibrin network.…”