title: Oral mucosa produces cytokines and factors influencing osteoclast activity and endothelial cell proliferation, in patients with osteonecrosis of jaw after treatment with zoledronic acid.
abstract: OBJECTIVE
  The intravenous injection of bisphosphonates, currently used as treatment for osteoporosis, bone Paget's disease, multiple myeloma, or bone metastases, can cause jaw bone necrosis especially in consequence of trauma. The present research aimed to clarify the mechanisms underlying bone necrosis, exploring involvement of the oral mucosa "in vivo."
  
  
  METHODS
  Specimens of oral mucosa were removed from bisphosphonate-treated patients with or without jaw bone necrosis. In mucosa specimens, expression was evaluated of: cytokines involved in the inflammatory process, factors involved in osteoclast activity, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin, a factor involved in cell proliferation, namely hydroxymethylglutaryl coenzyme A reductase, and a factor involved in angiogenesis, namely vascular endothelial growth factor (VEGF).
  
  
  RESULTS
  Interleukin (IL)-6 and the RANK/osteoprotegerin ratio were significantly elevated in mucosa from patients with versus without jaw necrosis, whereas hydroxymethylglutaryl coenzyme A reductase and VEGF were significantly decreased.
  
  
  CONCLUSIONS
  Our results suggest that mucosa, stimulated by bisphosphonate released from the bone, can contribute to the development of jaw necrosis, reducing VEGF, and producing IL-6 in consequence of hydroxymethylglutaryl coenzyme A reductase reduction. In turn, IL-6 stimulates osteoclast activity, as shown by the increased RANKL/osteoprotegerin ratio.
  
  
  CONCLUSIONS
  The results of this study suggest the importance of evaluating during bisphosphonate treatment the production of IL-6, RANKL, osteoprotegerin, and VEGF, in order to monitor the jaw osteonecrosis onset. To avoid repeated mucosa excisions, the determination of these factors could be carried out in crevicular fluid.
authors.affiliation: Oral Surgery Unit, Dentistry Section, Department of Biomedical Sciences and Human Oncology, Dental School, University of Turin, Via Nizza 262, 10126, Turin, Italy. marco.mozzati@libero.it
authors.forename: Marco
authors.initials: M
authors.lastname: Mozzati
authors.forename: Germana
authors.initials: G
authors.lastname: Martinasso
authors.forename: Marina
authors.initials: M
authors.lastname: Maggiora
authors.forename: Matteo
authors.initials: M
authors.lastname: Scoletta
authors.forename: Marta
authors.initials: M
authors.lastname: Zambelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Carossa
authors.forename: Manuela
authors.initials: M
authors.lastname: Oraldi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Muzio
authors.forename: Rosa Angela
authors.initials: RA
authors.lastname: Canuto
mesh_terms: D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy; D016022:Case-Control Studies; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D005883:Gingival Crevicular Fluid / Q000737:chemistry; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D007275:Injections, Intravenous / Q000009:adverse effects; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism* / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy; D010010:Osteoclasts / Q000502:physiology*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D015850:Interleukin-6; D053244:Osteoprotegerin; D053245:RANK Ligand; D042461:Vascular Endothelial Growth Factor A; D000077211:Zoledronic Acid; D006903:Hydroxymethylglutaryl CoA Reductases