title: Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.
abstract: Bisphosphonates (BPs) are analogues of pyrophosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF‑β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF‑β-induced promotion of cell viability, ii) the TGF‑β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF‑β-induced migratory activity of hGFs and iv) the expression level of TGF‑β type I receptor on the surfaces of hGFs, as well as the TGF‑β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF‑β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad‑dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level.
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ibi
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Chosa
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Kyakumoto
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kamo
authors.affiliation: Department of Oral and Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Reconstructive Oral and Maxillofacial Surgery, Iwate Medical University, Iwate 020-8505, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D005881:Gingiva / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000077211:Zoledronic Acid; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I