title: Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice.
abstract: Osteonecrosis of the jaw (ONJ) is a serious adverse event that occurs predominantly in patients on both antiresorptive and antineoplastic therapies. However, how these combination therapies are connected to the high frequency of ONJ in this particular patient population is unclear. This study's aim was to determine a mechanism of ONJ associated with the combination therapy of antiresorptives and chemotherapeutics. Mice received zoledronic acid (ZA) in conjunction with melphalan or dexamethasone. The maxillary first molars were extracted 3 weeks after the initiation of treatment and wound healing assessed at 4 weeks post-extractions using microcomputed tomography and immunohistochemistry. Mice receiving the combination treatment of ZA and melphalan developed ONJ-like lesions, while ONJ-like lesions were not found in mice on ZA or melphalan monotherapy, or the combination treatment of ZA and dexamethasone. ONJ lesions were characterized by a lack of epithelium, exposed necrotic bone, severe inflammatory cell infiltration, and minimal bone formation. Fluorescent immunohistochemistry showed that lymphatic vessel formation was significantly suppressed in ONJ-like lesions with a concomitant decrease in F4/80(+) macrophages expressing vascular endothelial growth factor C (VEGFC). Interestingly, significantly suppressed lymphatics were also found in the draining lymph nodes of mice on the combination treatment of ZA and melphalan. Thus, suppressed lymphangiogenesis was strongly associated with the development of ONJ-like lesions in the current study. Since lymphangiogenesis is critical in the resolution of inflammation during wound healing, inflammation control may serve as a potential strategy to prevent ONJ.
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA. kuroshima@nagasaki-u.ac.jp
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kuroshima
authors.forename: Junro
authors.initials: J
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000494:pharmacology; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology; D008558:Melphalan / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects; D020390:Tooth Socket / Q000000981:diagnostic imaging / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D042582:Vascular Endothelial Growth Factor C; D000077211:Zoledronic Acid; D008558:Melphalan
keywords: Lymphangiogenesis; Melphalan; Osteonecrosis of the jaw; Wound healing; Zoledronic acid