title: Bisphosphonates induce senescence in normal human oral keratinocytes.
abstract: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cancer patients, on the phenotypes of normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). When exposed to PAM at 10 µM, NHOK, not NHOF, underwent senescence: NHOK overexpressed senescence-associated β-galactosidase (SA-β-Gal), p16INK4A, IL-6, and IL-8. When exposed to a higher level (50 µM) of PAM, NHOK maintained senescent phenotypes, but NHOF underwent apoptosis. PAM-induced senescence in NHOK is mediated, in part, via geranylgeranylation of the mevalonate pathway. Our in vitro 3D oral mucosal tissue construction studies further demonstrated that PAM induced senescence and impaired re-epithelialization of oral mucosa. Analysis of these data indicates that premature senescence of oral mucosal cells and subsequent defective soft-tissue wound healing might be partly responsible for the development of BRONJ in individuals receiving PAM or other BPs.
authors.affiliation: UCLA School of Dentistry, Center for the Health Sciences, Room 43-091, 10833 Le Conte Ave, Los Angeles, CA 90095, USA. rkim@dentistry.ucla.edu
authors.forename: R H
authors.initials: RH
authors.lastname: Kim
authors.forename: R S
authors.initials: RS
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Williams
authors.forename: S
authors.initials: S
authors.lastname: Bae
authors.forename: J
authors.initials: J
authors.lastname: Woo
authors.forename: M
authors.initials: M
authors.lastname: Lieberman
authors.forename: J-E
authors.initials: JE
authors.lastname: Oh
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: K-H
authors.initials: KH
authors.lastname: Shin
authors.forename: M K
authors.initials: MK
authors.lastname: Kang
authors.forename: N-H
authors.initials: NH
authors.lastname: Park
mesh_terms: D017209:Apoptosis; D050071:Bone Density Conservation Agents / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D004164:Diphosphonates / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects*; D000077268:Pamidronate; D054876:Prenylation; D014945:Wound Healing / Q000187:drug effects
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077268:Pamidronate; D008798:Mevalonic Acid