Article
Tofacitinib promotes fundamental processes of bone healing including mesenchymal stromal cell recruitment and osteogenesis under hypoxia
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Authors
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Timo Gaber
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Justyna Pienczykowski
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Alexandra Damerau
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Moritz Pfeiffenberger
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Lisa Ehlers
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Frank Buttgereit
- Charité – Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
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Paula Hoff
- Endokrinologikum, Rheumatologie, Berlin
| Published: | February 5, 2019 |
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Outline
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Background: In 2060 every third will be aged 65 or older. This demographic development will lead to a higher incidence of surgical interventions (such as fracture treatment and arthroplasty) as a result of an impaired or delayed bone healing, a degenerative joint disease, osteoarthritis or osteoporosis. Moreover, inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GC) or NSAIDS negatively influence bone metabolism and fracture healing. Janus kinase (Jak) inhibition with tofacitinib has been demonstrated as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration such as recruitment of mesenchymal stromal cells (MSCs) and osteogenic differentiation is still elusive. Therefore, we hypothesize that tofacitinib promotes bone regeneration by enhancing invasion and osteogenic differentiation of MSCs even under pathophysiological hypoxia as a key feature of the fractur gap.
Methods: To study the effects of tofacitinib on MSC invasion and migration towards a high serum and TNFα gradient, we seeded fully characterized bone marrow-derived human MSCs in the presence of varying doses of tofacitinib (0-500 nM) on a collagen coated trans-well system for 24h under normoxia and hypoxia, respectively. Invaded and migrated cells were analyzed by cell staining and counting. To analyze the impact of tofacitinib on osteogenic differentiation of human MSCs, cells were grown in osteogenic cell culture media supplemented with varying doses of tofacitinib (0-500 nM) twice daily for three weeks. Cells were analyzed for calcium production by Alizarin Red staining and for the gene expression RUNX2 and COL1A1 by qPCR as markers of osteogenic differentiation.
Results: Jak inhibition by increasing doses of tofacitinib resulted in an increase of invaded and migrated MSCs under hypoxic incubation conditions but inhibited MSC migration and invasion under normoxia [Figure 2]. Similarly, we observed an increased calcium production as a marker of osteogenic differentiation under hypoxia which was enhanced with increasing doses of tofacitinib. In contrast, under normoxia tofacitinib did not influence calcium production.
Conclusion: Tofacitinib increases human MSC invasion/migration and osteogenic differentiation under hypoxia which is a key feature of the fractur gap. Thus, tofacitinib as an immunosuppressive drug promotes fundamental processes of bone regeneration. These results could in part explain the positive impact oftofacitinib on bone erosions. Additionally, we hypothesize that it will be unnecessary to stop this medication in case of fracture. Furthermore, positive effects on osteoporosis are likely.
