Cyclosporine A up-regulates Sonic hedgehog in gingiva: role of the up-regulation on gingival cell proliferation.
OBJECTIVE
Sonic hedgehog protein (SHH) is a mitogen that stimulates cell proliferation. Cyclosporine A enhances the proliferation of gingival cells; however, the relationships of SHH to cyclosporine A or to cyclosporine A-enhanced gingival cell proliferation have not been described.


METHODS
Here, we investigated SHH expression in gingiva in vitro and in vivo after cyclosporine A treatment and tested the effect of SHH inhibition on cyclosporine A-enhanced gingival fibroblast proliferation in vitro.


RESULTS
In human gingival fibroblasts, cyclosporine A treatment increased the expression of SHH transcripts and SHH protein, and stimulated cell proliferation; the addition of cyclopamine, an SHH signaling inhibitor, suppressed cyclosporine A-enhanced cell proliferation. Up-regulated expression of SHH and up-regulation of proliferating cell nuclear antigen transcripts and protein were observed in the edentulous gingiva of cyclosporine A-treated rats.


CONCLUSIONS
Cyclosporine A up-regulates gingival SHH expression in vitro and in vivo, and the inhibition of the SHH pathway counteracts the stimulatory effect of cyclosporine A on gingival fibroblast proliferation. Therefore, we suggest that SHH mediates a novel molecular mechanism for cyclosporine A-induced gingival complications.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, China; Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, China.
Y
Y
Chung
E
E
Fu
D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects*; D006801:Humans; D007575:Jaw, Edentulous / Q000473:pathology; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D023421:Models, Animal; D015513:Oncogene Proteins / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000187:drug effects; D015854:Up-Regulation; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D016335:Zinc Fingers / Q000187:drug effects
D053823:Hedgehog Proteins; D008934:Mitogens; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; C509239:SHH protein, human; C546888:Shh protein, rat; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D016572:Cyclosporine; C000541:cyclopamine
cell proliferation; cyclosporine; fibroblasts; sonic hedgehog