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 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.
Highlights
The seronegative spondyloarthropathies (SpA) encompass Ankylosing Spondylitis (AS), its non-radiographic predecessor and psoriatic arthritis (PsA) (Psoriatic Arthritis), including peripheral and axial disease
Tofacitinib had no effect on bone marrow mesenchymal stem cells (MSCs)
To study whether tofacitinib affects the multi-lineage potential of MSCs, we studied its effect in osteogenic, chondrogenic and adipogenic differentiation assays
Summary
The seronegative spondyloarthropathies (SpA) encompass Ankylosing Spondylitis (AS), its non-radiographic predecessor and PsA (Psoriatic Arthritis), including peripheral and axial disease. Cytokines including TNF and IL-17A are pivotal in the pathogenesis of the seronegative SpA in both experimental settings and, more importantly, in humans, as demonstrated by the success of cytokine targeting [1]. A peculiar aspect of successful antiTNF therapy in well-established AS was progressive new bone formation over the following years [2]. Skeletal tissue repair and remodeling responses are orchestrated by tissue-resident stromal cells, including mesenchymal stem cells (MSCs) which have been identified in the synovium, periosteum, bone marrow and synovial fluid [4,5,6,7,8] and have been reported at Immuno 2021, 1, 545–557. It has been established that animal models of SpA have resident immune cell populations at the enthesis and, in particular, immune cells that produce abundant IL-17A [12,13], where this cytokine can modulate aberrant bone formation reactions. Animal models of SpA, as well as showing new bone formation, show decreased bone marrow adipose tissue (BMAT) [15]
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