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

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 SpA 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 mononucleated 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 (dosages ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cy-tokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by tofacitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and osteogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human entheseal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofa-citinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis the relevance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA

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Tofacitinib Blocks Entheseal Lymphocyte Activation and modulates MSC adipogenesis but does not directly affect chondro- and osteogenesis

10.20944/preprints202107.0494.v2 ◽

2021 ◽

Author(s):

Tobias Russell ◽

Hannah Rowe ◽

Charlie Bridgewood ◽

Richard Cuthbert ◽

Abdulla Watad ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

T Cells ◽

Bone Formation ◽

Cd8 T Cells ◽

Stromal Cell ◽

Bone Marrow Stromal Cell ◽

New Bone Formation ◽

Marrow Stromal Cell

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.

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

10.20944/preprints202107.0494.v3 ◽

2021 ◽

Author(s):

Tobias Russell ◽

Hannah Rowe ◽

Charlie Bridgewood ◽

Richard J. Cuthbert ◽

Abdulla Watad ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

T Cells ◽

Bone Formation ◽

Cd8 T Cells ◽

Stromal Cell ◽

Bone Marrow Stromal Cell ◽

New Bone Formation ◽

Marrow Stromal Cell

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.

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

Immuno ◽

10.3390/immuno1040038 ◽

2021 ◽

Vol 1 (4) ◽

pp. 545-557

Author(s):

Tobias Russell ◽

Hannah Rowe ◽

Charlie Bridgewood ◽

Richard J. Cuthbert ◽

Abdulla Watad ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Stem Cell ◽

Bone Formation ◽

Cd8 T Cells ◽

Stromal Cell ◽

Bone Marrow Stromal Cell ◽

New Bone Formation ◽

Marrow Stromal Cell

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 cell (MSCs) function, including osteogenesis, since post inflammation new bone formation occurs under these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were investigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in tofacitinib treated (1000 nM) peri-entheseal bone (PEB) and peripheral blood mononuclear cells (PBMC) using ELISA. Bone marrow stromal cell-derived mesenchymal stem cell (MSC) colony forming units (CFU-F) and multi-lineage potential were evaluated using tofacitinib (dosages ranging between 100, 500, 1000 and 10,000 nM). Results: Induced IL-17A and TNF cytokine production from both entheseal CD4+ T-cells and CD8+ T-cells was effectively inhibited by tofacitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and osteogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained areas. Conclusion: Inducible IL-17A and TNF production by healthy human entheseal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofacitinib did not impact MSC osteogenesis, but stimulated in vitro MSC adipogenesis, the relevance of which needs further evaluation given that the adipocytes are associated with new bone formation in SpA.

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