Naslov
Cellular and molecular targets of Fas-dependent inflammation and bone resorption in arthritis

Autori
Kovačić, Nataša

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Skup
Annual Meeting of the Croatian Immunological Society 2018

Mjesto i datum
Zadar, Hrvatska, 19.10.2018. - 20.10.2018

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Fas, inflammation, osteoresorption, arthritis. Midline 1

Sažetak
Fas/Fas ligand system is a well described regulator of the immune system homeostasis, and involved in the pathogenesis of various immune disorders. This pleiotropic system acts on a wide range of cell types, not only by induction of apoptosis, but also via non-apoptotic signals regulating their proliferation, differentiation and survival. Our group has long been studying the role of this system in the regulation of bone cell apoptosis, differentiation and function, and established that deficiency in either Fas or its ligand has a bone-sparing effect, promoting bone formation over resorption, especially under bone- compromising conditions such as estrogen deficiency and inflammation. We were particularly interested in its role in rheumatoid arthritis (RA) known for its bone-destructive potential, so we analyzed the course of antigen-induced arthritis (AIA, a mouse model of RA) in mice deficient for Fas (Fas –/–), and found less inflammation, alleviated synovial thickening and lack of bone resorption. To evaluate potential mechanisms and downstream molecules involved in reduction of disease activity, we first assessed the cellular composition of the infiltrate in the affected synovia. Amongst the altered populations, the earliest bone and cartilage progenitors (CD45– CD31–TER119–CD200+CD90.1–CD105–) were preserved in Fas –/–mice with ameliorated AIA, in contrast to their reduction in wild-type mice with destructive AIA. Those cells express high levels of Fas and their removal by Fas ligation in arthritis may compromise bone forming regenerative capacity. Proportion of CD200+ cells is also lower in synovia from RA patients in comparison to healthy controls. In addition, Fas inactivation blocked accumulation of myeloid cells (CD11b+Gr1+) in synovial compartment of mice with arthritis. Based on comparison of gene expression, Fas –/– synovial myeloid cells exhibit similar profile to wild-type myeloid cells. Differential expression analysis identified low expression of Midline 1 (Mid 1) gene. Mid 1 encodes a microtubule associated ubiquitine- ligase E3, which enhances the removal of protein phosphatase 2A (PP2A), responsible for suppression of inflammation. Lower expression and function of Mid 1 has been reported in TRAIL deficient mice, pointing to its downstream position to death receptor signaling. Further functional investigation of this gene and its product may reveal new targets for improved therapeutic management of arthritis.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA