Loss of ephrinB1 in osteogenic progenitor cells impedes endochondral ossification and compromises bone strength integrity during skeletal development.
The EphB receptor tyrosine kinase family and their ephrinB ligands have been implicated as mediators of skeletal development and bone homeostasis in humans, where mutations in ephrinB1 contribute to frontonasal dysplasia and coronal craniosynostosis. In mouse models, ephrinB1 has been shown to be a critical factor mediating osteoblast function. The present study examined the functional importance of ephrinB1 during endochondral ossification using the Cre recombination system with targeted deletion of ephrinB1 (EfnB1fl/fl) in osteogenic progenitor cells, under the control of the osterix (Osx:Cre) promoter. The Osx:EfnB1-/-mice displayed aberrant bone growth during embryonic and postnatal skeletal development up to 4weeks of age, when compared to the Osx:Cre controls. Furthermore, compared to the Osx:Cre control mice, the Osx:EfnB1-/-mice exhibited significantly weaker and less rigid bones, with a reduction in trabecular/ cortical bone formation, reduced trabecular architecture and a reduction in the size of the growth plates at the distal end of the femora from newborn through to 4weeks of age. The aberrant bone formation correlated with increased numbers of tartrate resistant acid phosphatase positive osteoclasts and decreased numbers of bone lining osteoblasts in 4week old Osx:EfnB1-/-mice, compared to Osx:Cre control mice. Taken together, these observations demonstrate the importance of ephrinB1 signalling between cells of the skeleton required for endochondral ossification.
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Thao M
TM
Nguyen
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Division of Haematology, SA Pathology, Adelaide, SA, Australia.
Agnieszka
A
Arthur
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
Sharon
S
Paton
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Sarah
S
Hemming
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
Romana
R
Panagopoulos
School of Mechanical Engineering, University of Adelaide, Adelaide, Australia.
John
J
Codrington
St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Vic, Australia.
Carl R
CR
Walkley
South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
Andrew C W
AC
Zannettino
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia. Electronic address: stan.gronthos@adelaide.edu.au.
Stan
S
Gronthos
D000818:Animals; D001842:Bone and Bones / Q000196:embryology / Q000502:physiology*; D000071556:Cancellous Bone / Q000254:growth & development; D020219:Chondrogenesis; D000071538:Cortical Bone / Q000254:growth & development; D047108:Embryonic Development; D036387:Ephrin-B1 / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D006132:Growth Plate / Q000254:growth & development; D008297:Male; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D011401:Promoter Regions, Genetic; D000076182:Sp7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D016019:Survival Analysis
D036387:Ephrin-B1; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse
Chondrocytes; Endochondral ossification; Eph/ephrin; Osteoclasts; Osteoprogenitors; Osterix