dc.contributor.author
Gaber, Timo
dc.contributor.author
Brinkman, Antonia Clara Katharina
dc.contributor.author
Pienczikowski, Justyna
dc.contributor.author
Diesing, Karoline
dc.contributor.author
Damerau, Alexandra
dc.contributor.author
Pfeiffenberger, Moritz
dc.contributor.author
Lang, Annemarie
dc.contributor.author
Ohrndorf, Sarah
dc.contributor.author
Burmester, Gerd-Rüdiger
dc.contributor.author
Buttgereit, Frank
dc.contributor.author
Hoff, Paula
dc.date.accessioned
2020-03-26T12:49:08Z
dc.date.available
2020-03-26T12:49:08Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/27031
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-26792
dc.description.abstract
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.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
bone healing
en
dc.subject
hMSC-migration
en
dc.subject
chondrogenic differentiation
en
dc.subject
osteogenic differentiation
en
dc.subject
osteoclast differentiation
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
865
dcterms.bibliographicCitation.doi
10.3390/ijms21030865
dcterms.bibliographicCitation.journaltitle
International Journal of Molecular Sciences
dcterms.bibliographicCitation.originalpublishername
MDPI AG
dcterms.bibliographicCitation.volume
21
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
32013232
dcterms.isPartOf.eissn
1422-0067