Bisphosphonates Inhibit Expression of p63 by Oral Keratinocytes

被引:23
|
作者
Scheller, E. L. [2 ]
Baldwin, C. M. [1 ]
Kuo, S. [4 ]
D'Silva, N. J. [1 ,3 ]
Feinberg, S. E. [4 ]
Krebsbach, P. H. [2 ]
Edwards, P. C. [1 ]
机构
[1] Univ Michigan, Sch Med, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Sch Med, Dept Biol & Mat Sci, Ann Arbor, MI USA
[3] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA
[4] Univ Michigan, Sch Dent, Dept Oral & Maxillofacial Surg, Ann Arbor, MI 48109 USA
关键词
osteonecrosis; oral pathology; gingival; epithelia; keratinocytes; zoledronic acid; MEVALONATE PATHWAY; BONE-RESORPTION; CACO-2; CELLS; STEM-CELLS; IN-VITRO; ALENDRONATE; OSTEONECROSIS; MACROPHAGES; EQUIVALENT; APOPTOSIS;
D O I
10.1177/0022034511407918
中图分类号
R78 [口腔科学];
学科分类号
1003 ;
摘要
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 amino-bisphosphonates; 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 bisphosphonate-treated 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 mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.
引用
收藏
页码:894 / 899
页数:6
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