Date: Sunday, November 8, 2015
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Inflammation and new bone formation at entheseal sites are hallmarks of spondyloarthritis (SpA). As TNF inhibition has only limited impact on new bone formation, there is a clear need for new SpA targets.
Objectives: To assess the role of JAK-STAT inhibition in in vitro and in vivo models that mimic specific SpA aspects with special emphasis on entheseal inflammation and new bone formation.
Mice with a specific deletion of A20 (inhibitor of the NF-kB signaling pathway) in myeloid cells (A20myelKO) were administered tofacitinib twice a day for 14 days in one experiment and for 21 days in a second experiment. They were scored clinically and afterwards sacrificed for histopathological analysis. Reporter assays with STAT- and NF-kB dependent reporters were conducted in presence or absence of A20. Synovial fibroblasts of A20 deficient mice were stimulated with TNF and the ability of tofacitinib to modulate release of a number of proinflammatory mediators including IL-6, MMP-3, MMP-13 was monitored. Entheseal inflammation, cell proliferation and new bone formation leading to joint ankylosis was studied in the spontaneous arthritis model in aging male DBA/1 mice. Mice were treated with tofacitinib at week 10 of age and continued for 14 weeks and evaluated for clinical signs of arthritis bi-weekly. In addition the effect tofacitinib on inflammation associated new bone formation was studied in the collagen-antibody induced arthritis(CAIA) model. pSTAT3 expression was determined in injured human entheses and the effect of tofacitinib was evaluated in normal human MSC induced osteogenesis.
We found that the earliest signs of inflammation in A20myelKO mice occur at the synovio-entheseal complex of the hindpaws with clear signs of enthesitis. In addition to its previously described role as negative regulator of NF-kB, we found an inhibitory role for A20 on Stat-1 induction. pSTAT3 expression was demonstrated by IHC at injured human entheses. We therefore assessed the role of JAK-STAT inhibition with tofacitinib and found a profound reduction of enthesitis by histopathology (p<0.05). In addition, tofacitinib completely suppressed TNF induced release of known proinflammatory mediators such as IL-6, MMP-13 and MMP-3. In the spontaneous ankylosing enthesitis model we noticed a steady increase in incidence and severity in the control group, but the incidence was delayed in the tofacinitib treated groups in a dose-dependent way. Severity of disease was significantly different with the high dosage of tofacitinib compared to control mice. Furthermore, we observed a significant effect of tofacitinb on the amount of new bone formation in the resolution phase collagen antibody induced arthritis (p<0.05). However, no adverse effect of tofocitinib was evident during in vitro MSC osteogenic differentiation.
Our results highlight the potential of JAK-STAT inhibition to modulate inflammation and new bone formation in SpA. Interestingly, enthesitis occurring in A20myelKO mice proceeds independently from TNF, which highlights that the effects of JAK-STAT inhibition also occur beyond TNF.
To cite this abstract in AMA style:Lories R, De Wilde K, Heritage K, Cuthbert R, Jones E, Debusschere K, McGonagle D, Elewaut D. Tofacitinib Inhibits Inflammation and New Bone Formation in Murine Spondyloarthritis but Does Not Adversely Inhibit Normal Human MSC Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/tofacitinib-inhibits-inflammation-and-new-bone-formation-in-murine-spondyloarthritis-but-does-not-adversely-inhibit-normal-human-msc-function/. Accessed September 17, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-inhibits-inflammation-and-new-bone-formation-in-murine-spondyloarthritis-but-does-not-adversely-inhibit-normal-human-msc-function/