Preprint Article Version 3 Preserved in Portico This version is not peer-reviewed

Tofacitinib Blocks Entheseal Lymphocyte Activation and Modulates MSC Adipogenesis but Does not Directly Affect Chondro- and Osteogenesis

Tobias Russell
ORCID logo ,
Hannah Rowe
,
Charlie Bridgewood
ORCID logo ,
Richard J. Cuthbert
,
Abdulla Watad
ORCID logo ,
Darren Newton
,
Elena Jones
,
Dennis McGonagle
*
Version 1 : Received: 16 July 2021 / Approved: 21 July 2021 / Online: 21 July 2021 (14:38:32 CEST)
Version 2 : Received: 17 September 2021 / Approved: 21 September 2021 / Online: 21 September 2021 (14:36:07 CEST)
Version 3 : Received: 8 October 2021 / Approved: 12 October 2021 / Online: 12 October 2021 (20:39:00 CEST)

A peer-reviewed article of this Preprint also exists.

Russell, T.; Rowe, H.; Bridgewood, C.; Cuthbert, R.J.; Watad, A.; Newton, D.; Jones, E.; McGonagle, D. Tofacitinib Blocks Entheseal Lymphocyte Activation and Modulates MSC Adipogenesis, but Does Not Directly Affect Chondro- and Osteogenesis. Immuno 2021, 1, 545-557. Russell, T.; Rowe, H.; Bridgewood, C.; Cuthbert, R.J.; Watad, A.; Newton, D.; Jones, E.; McGonagle, D. Tofacitinib Blocks Entheseal Lymphocyte Activation and Modulates MSC Adipogenesis, but Does Not Directly Affect Chondro- and Osteogenesis. Immuno 2021, 1, 545-557.

Abstract

Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key disease associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis, since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononuclear cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosag-es ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cytokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by to-facitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and oste-ogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human enthe-seal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofacitinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis, the rele-vance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA.

Keywords

Tofacitinib; JAK-STAT; chondrogenesis; psoriatic arthritis; spondyloarthritis

Subject

Biology and Life Sciences, Immunology and Microbiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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