The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis ...The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.展开更多
Magnesium(Mg)–based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing,e.g.as a suture anchor.Due to their mechanical properties and biocompat...Magnesium(Mg)–based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing,e.g.as a suture anchor.Due to their mechanical properties and biocompatibility,they may replace titanium or stainless-steel implants,commonly used in orthopedic field.Nevertheless,patient safety has to be assured by finding a long-term balance between metal degradation,osseointegration,bone ultrastructure adaptation and element distribution in organs.In order to determine the implant behavior and its influence on bone and tissues,we investigated two Mg alloys with gadolinium contents of 5 and 10 wt percent in comparison to permanent materials titanium and polyether ether ketone.The implants were present in rat tibia for 10,20 and 32 weeks before sacrifice of the animal.Synchrotron radiation-based micro computed tomography enables the distinction of features like residual metal,degradation layer and bone structure.Additionally,X-ray diffraction and X-ray fluorescence yield information on parameters describing the bone ultrastructure and elemental composition at the bone-to-implant interface.Finally,with element specific mass spectrometry,the elements and their accumulation in the main organs and tissues are traced.The results show that Mg-xGd implants degrade in vivo under the formation of a stable degradation layer with bone remodeling similar to that of Ti after 10 weeks.No accumulation of Mg and Gd was observed in selected organs,except for the interfacial bone after 8 months of healing.Thus,we confirm that Mg-5Gd and Mg-10Gd are suitable material choices for bone implants.展开更多
基金supported by funding from the Medical Research Council (MRC) through the WIMM Strategic Alliance (G0902418 and MC_UU_12025) and to E. Y.J. (G9900061),the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (AOMW)the Wellcome Trust (Project Grant 093329 to AOMW and SRFT+8 种基金Investigator Award 102731 to AOMWgrant 090532/Z/09/Z supporting the Wellcome Trust Centre for Human Genetics)supported by the Crohn’s & Colitis Foundation of America (CCFA)the Leona M. and Harry B. Helmsley Charitable Trustfunded by the NIHR Oxford Biomedical Research Centresupported by the Deutsche Forschungsgemeinschaft (SCHW1730/1-1)supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn (grant number SFB841 to F.K., D.S.-A., and S.R.-J.SFB877 to S.R.-J.)the Cluster of Excellence “Inflammation at Interfaces” to S.R.-J.
文摘The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.
基金This publication is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sk lodowska-Curie grant,agreement No 811226Röntgen-Angström Cluster in project SynchroLoad(05K16CGA)+5 种基金Swedish Research Council 2015-06109German Bundesministerium für Bildung und Forschung in project MgBone(05K16CGB)We acknowledge DESY(Hamburg,Germany),a member of the Helmholtz Association HGF,for the provision of experimental facilities.Parts of this research were carried out at PETRA IIIThe authors would like to thank Diamond Light Source for beamtime(proposal MG25078)Miguel Gomez Gonzalez and Julia Parker for assistance during the experiment at the I14 beamline and during the data analysisThis research was carried out in collaboration with the Quantitative Bio Element Analysis and Mapping(QBEAM)Center at Michigan State University and The National Research Resource for Quantitative Elemental Mapping for the Life Sciences(QE-Map)under Grant P41 GM135018(as well as Grant S10OD026786)from the National Institute of General Medical Sciences of the National Institutes of Health.
文摘Magnesium(Mg)–based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing,e.g.as a suture anchor.Due to their mechanical properties and biocompatibility,they may replace titanium or stainless-steel implants,commonly used in orthopedic field.Nevertheless,patient safety has to be assured by finding a long-term balance between metal degradation,osseointegration,bone ultrastructure adaptation and element distribution in organs.In order to determine the implant behavior and its influence on bone and tissues,we investigated two Mg alloys with gadolinium contents of 5 and 10 wt percent in comparison to permanent materials titanium and polyether ether ketone.The implants were present in rat tibia for 10,20 and 32 weeks before sacrifice of the animal.Synchrotron radiation-based micro computed tomography enables the distinction of features like residual metal,degradation layer and bone structure.Additionally,X-ray diffraction and X-ray fluorescence yield information on parameters describing the bone ultrastructure and elemental composition at the bone-to-implant interface.Finally,with element specific mass spectrometry,the elements and their accumulation in the main organs and tissues are traced.The results show that Mg-xGd implants degrade in vivo under the formation of a stable degradation layer with bone remodeling similar to that of Ti after 10 weeks.No accumulation of Mg and Gd was observed in selected organs,except for the interfacial bone after 8 months of healing.Thus,we confirm that Mg-5Gd and Mg-10Gd are suitable material choices for bone implants.
