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Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris).
Bone 2020; 130:115141BONE

Abstract

OBJECTIVE

Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone.

METHODS

At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 μg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses.

RESULTS

40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats.

CONCLUSIONS

Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.

Authors+Show Affiliations

Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: jgmesser@ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: evelynjcastillo@ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: abelabra@ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: jjiron@ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: ronniei@ufl.edu.Research Service, VA Medical Center, Gainesville, FL, United States of America; Division of Endocrinology, Diabetes, and Metabolism, University of Florida College of Medicine, Gainesville, FL, United States of America. Electronic address: Joshua.yarrow@medicine.ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: sthomas101@ufl.edu.Research Service, VA Medical Center, Gainesville, FL, United States of America.Research Service, VA Medical Center, Gainesville, FL, United States of America.Department of Pediatrics, College of Medicine, UF, United States of America. Electronic address: marda@ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America.University of Michigan, Ann Arbor, MI, United States of America. Electronic address: cvanpoz@med.umich.edu.Department of Oral & Maxillofacial Diagnostic Sciences, College of Dentistry, UF, United States of America. Electronic address: IBHATTACHARYYA@dental.ufl.edu.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: kimmeldb@comcast.net.Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America. Electronic address: aguirrej@ufl.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31707108

Citation

Messer, J G., et al. "Anti-vascular Endothelial Growth Factor Antibody Monotherapy Causes Destructive Advanced Periodontitis in Rice Rats (Oryzomys Palustris)." Bone, vol. 130, 2020, p. 115141.
Messer JG, Castillo EJ, Abraham AM, et al. Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris). Bone. 2020;130:115141.
Messer, J. G., Castillo, E. J., Abraham, A. M., Jiron, J. M., Israel, R., Yarrow, J. F., ... Aguirre, J. I. (2020). Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris). Bone, 130, p. 115141. doi:10.1016/j.bone.2019.115141.
Messer JG, et al. Anti-vascular Endothelial Growth Factor Antibody Monotherapy Causes Destructive Advanced Periodontitis in Rice Rats (Oryzomys Palustris). Bone. 2020;130:115141. PubMed PMID: 31707108.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris). AU - Messer,J G, AU - Castillo,E J, AU - Abraham,A M, AU - Jiron,J M, AU - Israel,R, AU - Yarrow,J F, AU - Thomas,S, AU - Reynolds,M C, AU - Wnek,R D, AU - Jorgensen,M, AU - Wanionok,N, AU - Van Poznak,C, AU - Bhattacharyya,I, AU - Kimmel,D B, AU - Aguirre,J I, Y1 - 2019/11/07/ PY - 2019/06/07/received PY - 2019/10/15/revised PY - 2019/11/04/accepted PY - 2021/01/01/pmc-release PY - 2019/11/11/pubmed PY - 2019/11/11/medline PY - 2019/11/11/entrez KW - Anti-angiogenic KW - Jaw KW - Oncology KW - Oral diseases KW - Osteonecrosis SP - 115141 EP - 115141 JF - Bone JO - Bone VL - 130 N2 - OBJECTIVE: Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. METHODS: At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 μg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. RESULTS: 40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. CONCLUSIONS: Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/31707108/Anti-vascular_endothelial_growth_factor_antibody_monotherapy_causes_destructive_advanced_periodontitis_in_rice_rats_(Oryzomys_palustris) L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(19)30435-1 DB - PRIME DP - Unbound Medicine ER -