Bisphosphonates inhibit expression of p63 by oral keratinocytes

E. L. Scheller, C. M. Baldwin, S. Kuo, N. J. D'Silva, S. E. Feinberg, P. H. Krebsbach, Paul Edwards

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of aminobisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated control individuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonatetreated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8 ± 1.1% and 31.9 ± 5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonatepathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.

Original languageEnglish (US)
Pages (from-to)894-899
Number of pages6
JournalJournal of Dental Research
Volume90
Issue number7
DOIs
StatePublished - Jul 2011
Externally publishedYes

Fingerprint

Osteonecrosis
zoledronic acid
Diphosphonates
Keratinocytes
Jaw
Stem Cells
Epithelium
Bone and Bones
Mevalonic Acid
Mouth Mucosa
Connective Tissue
Small Interfering RNA
Epithelial Cells
Macrophages
Wounds and Injuries
In Vitro Techniques
Therapeutics

Keywords

  • Epithelia
  • Gingival
  • Keratinocytes
  • Oral pathology
  • Osteonecrosis
  • Zoledronic acid

ASJC Scopus subject areas

  • Dentistry(all)

Cite this

Scheller, E. L., Baldwin, C. M., Kuo, S., D'Silva, N. J., Feinberg, S. E., Krebsbach, P. H., & Edwards, P. (2011). Bisphosphonates inhibit expression of p63 by oral keratinocytes. Journal of Dental Research, 90(7), 894-899. https://doi.org/10.1177/0022034511407918

Bisphosphonates inhibit expression of p63 by oral keratinocytes. / Scheller, E. L.; Baldwin, C. M.; Kuo, S.; D'Silva, N. J.; Feinberg, S. E.; Krebsbach, P. H.; Edwards, Paul.

In: Journal of Dental Research, Vol. 90, No. 7, 07.2011, p. 894-899.

Research output: Contribution to journalArticle

Scheller, EL, Baldwin, CM, Kuo, S, D'Silva, NJ, Feinberg, SE, Krebsbach, PH & Edwards, P 2011, 'Bisphosphonates inhibit expression of p63 by oral keratinocytes', Journal of Dental Research, vol. 90, no. 7, pp. 894-899. https://doi.org/10.1177/0022034511407918
Scheller EL, Baldwin CM, Kuo S, D'Silva NJ, Feinberg SE, Krebsbach PH et al. Bisphosphonates inhibit expression of p63 by oral keratinocytes. Journal of Dental Research. 2011 Jul;90(7):894-899. https://doi.org/10.1177/0022034511407918
Scheller, E. L. ; Baldwin, C. M. ; Kuo, S. ; D'Silva, N. J. ; Feinberg, S. E. ; Krebsbach, P. H. ; Edwards, Paul. / Bisphosphonates inhibit expression of p63 by oral keratinocytes. In: Journal of Dental Research. 2011 ; Vol. 90, No. 7. pp. 894-899.
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