title: Development of oral osteomucosal tissue constructs in vitro and localization of fluorescently-labeled bisphosphonates to hard and soft tissue.
abstract: Bisphosphonates (BPs) are anti-resorptive agents commonly used to treat bone-related diseases; however, soft tissue-related side-effects are frequently reported in some BP users, such as oral or gastrointestinal (GI) ulcerations. BPs are stable analogs of pyrophosphate and have high affinity to hydroxyapatite, allowing them to bind to the bone surfaces and exert suppressive effects on osteoclast functions. However, the underlying mechanisms as to how bone-seeking BPs also exert cytotoxic effects on soft tissue remain unknown. In the present study, we investigated the localization of nitrogen-containing BPs (N-BPs) in hard and soft tissue using fluorescently-labeled N-BPs in vitro. We developed osteomucosal tissue constructs in vitro to recapitulate the hard and soft tissue of the oral cavity. A histological examination of the osteomucosal tissue constructs revealed a differentiated epithelium over the bone containing osteocytes and the periosteum, similar to that observed in the rat palatal tissues. Following treatment with the fluorescently-labeled bisphosphonate, AF647-ZOL, the osteomucosal constructs exhibited fluorescent signals, not only in the bone, but also in the epithelium. No fluorescent signals were observed from the control- or ZOL-treated constructs, as expected. Collectively, the data from the present study suggest that N-BPs localize to epithelial tissue and that such a localization and subsequent toxicity of N-BPs may be associated, at least in part, with soft tissue-related side-effects.
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Shuting
authors.initials: S
authors.lastname: Sun
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Aghaloo
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Ju-Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D066298:In Vitro Techniques; D009061:Mouth Mucosa / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats
chemical_list: D004164:Diphosphonates