title: Evaluation of the therapeutic effects of conditioned media from mesenchymal stem cells in a rat bisphosphonate-related osteonecrosis of the jaw-like model.
abstract: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined as an exposed necrotic bone in the oral cavity that does not heal after appropriate intervention for >8weeks with present or previous bisphosphonate treatment in the absence of radiotherapy. Until now, although several risk factors, including invasive dental procedures, infection, mechanical trauma to the jawbone, and concomitant use of immunosuppressive and chemotherapy drugs have been implicated in the etiology of BRONJ, its underlying mechanisms and treatments remain largely unknown. A study recently showed that intravenous administration of mesenchymal stem cells (MSCs) improved BRONJ, and it was hypothesized that paracrine effects by secretomes from MSCs are the main constituent. Here we used rat BRONJ models to examine the therapeutic effects with serum-free conditioned media from human MSCs (MSC-CM), including various secretomes. We showed that MSC-CM has protected rat MSCs and rat osteoclasts. MSC-CM enhanced the expression of osteogenic-related genes and neovascularization-related genes by real-time reverse-transcriptase polymerase chain reaction analysis in in vitro study. In in vivo study, 5-week-old Wistar/ST male rats received zoledronate (35μg/kg/week) and dexamethasone (1mg/kg/day) subcutaneously for 2weeks. Unilateral maxillary molars were then extracted. Two weeks later, rats were divided into non-treatment, serum-free Dulbecco's modified Eagle's medium, and MSC-CM groups. In the MSC-CM group, the open alveolar sockets in 63% of the rats with BRONJ healed with complete soft tissue coverage and socket bones, whereas the exposed necrotic bone with inflamed soft tissue remained in the other groups. Histological analysis showed new bone formation and the appearance of osteoclasts in the MSC-CM group. Osteoclasts were significantly reduced in the non-treatment group. Thus, we concluded that the antiapoptotic and antiinflammatory effects of MSC-CM dramatically regulated the turnover of local bone and indicated therapeutic effects on BRONJ.
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, 3-1-1 Maidashi, Fukuoka 812-8582, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: k.ogata@dent.kyushu-u.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: w-kat@med.nagoya-u.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Katagiri
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: masashi@med.nagoya-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Osugi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: takamasa@med.nagoya-u.ac.jp.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: sugimuray@med.nagoya-u.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sugimura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: hibihi@med.nagoya-u.ac.jp.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hibi
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, 3-1-1 Maidashi, Fukuoka 812-8582, Japan. Electronic address: seiji@dent.kyushu-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: mueda@med.nagoya-u.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004164:Diphosphonates / Q000009:adverse effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D011859:Radiography; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D004164:Diphosphonates; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D000077211:Zoledronic Acid; D003907:Dexamethasone
keywords: Bisphosphonate-related osteonecrosis; Conditioned media; Osteoclasts; Osteogenesis; Paracrine effects; Secretome