Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, 10117 Berlin, Germany.
Int J Mol Sci. 2020 Jan 29;21(3):865. doi: 10.3390/ijms21030865.
Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10-100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.
炎症性疾病（如类风湿关节炎，RA）和使用糖皮质激素（GCs）或非甾体抗炎药（NSAIDs）进行抗炎治疗会对骨骼代谢和骨折愈合产生负面影响。托法替尼（一种 Janus 激酶[JAK]抑制剂）已被证明在治疗 RA 中具有强大的抗炎治疗作用，但它对骨再生基本过程的影响目前存在争议，至少部分原因尚不清楚。因此，在这项研究中，我们旨在研究托法替尼对骨愈合过程的影响，重点关注人间充质基质细胞（hMSCs）向骨折间隙炎症微环境中的募集、软骨生成、成骨和破骨细胞生成。我们在低氧条件下进行了分析，以模拟体内骨折间隙的情况。我们证明，托法替尼在低氧条件下可剂量依赖性地促进 hMSCs 的募集，但在常氧条件下抑制 hMSCs 的募集。关于 hMSCs 的软骨分化，我们证明在治疗相关剂量 10-100 nM 下，托法替尼不会抑制细胞存活。此外，托法替尼可剂量依赖性地增强 hMSCs 的成骨分化，并减少破骨细胞分化和活性。我们从数据中得出结论，托法替尼可能通过促进 hMSCs 募集到骨折间隙的低氧微环境中来影响骨愈合，但不干扰骨折愈合过程中软愈伤组织阶段的软骨形成阶段。我们假设托法替尼可能会促进骨形成并减少骨吸收，这部分解释了托法替尼对 RA 骨侵蚀的积极影响。因此，我们假设在骨折时无需停止这种药物，并建议其对骨质疏松症有积极影响。
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