Bisphosphonate-related osteonecrosis induced change in alveolar bone architecture in rats with participation of Wnt signaling

• Published in: Clinical oral investigations Vol. 25; no. 2; pp. 673 - 682
• Main Authors: de Sousa Ferreira, Vanessa Costa, Lopes, Amanda Pimentel, Alves, Nicholas Militão, Sousa, Fatima Regina Nunes, Pereira, Karuza Maria Alves, Gondim, Delane Viana, Girão, Vírginia Claúdia Carneiro, Leitão, Renata Ferreira Carvalho, Goes, Paula
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2021; Springer Nature B.V
• Subjects: Alveolar bone; Animal models; Animals; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents - toxicity; Bone healing; Caspase-3; Collagen (type I); Dentistry; Diphosphonates - toxicity; Dkk1 protein; Female; IL-1β; Immunohistochemistry; Inflammation; Jaw; Maxilla; Medicine; Molars; Original Article; Osteocytes; Osteonecrosis; Rats; Rats, Wistar; Scanning electron microscopy; Tumor necrosis factor-α; Wnt protein; Wnt Signaling Pathway; Zoledronic acid; Zoledronic Acid - toxicity; β-Catenin; Bone architecture; Zoledronic acid; Wnt signaling; Osteonecrosis; Inflammation; Bisphosphonates
• ISSN: 1432-6981; 1436-3771
• DOI: 10.1007/s00784-020-03551-7

Objective This work aimed to study the role of inflammation in medication-related osteonecrosis of the jaw (MRONJ) in rats with focus on Wnt signaling. Methods A total of 36 female Wistar rats (12 weeks ± 200 g) were divided into 2 groups ( n  = 6) in 3 experiments: saline (SAL) and zoledronic acid (ZOL). For MRONJ induction, rats received 0.1 mg/kg of ZOL (ip) 3×/week for 9 weeks. Animals from the SAL group received 0.1 mg/kg of 0.9% SAL, ip 3×/week for 9 weeks. On the 8th week, 3 left upper molars were extracted, and on the 11th week, they were euthanized. Maxillae were evaluated by macroscopic and histopathological analyses; scanning electron microscopy (SEM); immunohistochemistry for DKK-1, Wnt 10b, and caspase-3; and Raman spectrometry. Gingiva was also collected for TNF-α e IL-1β quantification. Results Bone necrosis was confirmed by healing impairment, reduced number of viable osteocytes, increased caspase-3 immunoexpression, and increased number of empty lacunae ( p  < 0.05). ZOL enhanced inflammation and increased gingival levels of IL-1β and TNF-α ( p  < 0.05). Irregular indentations were seen on bone after ZOL administration. Bone necrosis was marked by reduced amount of total and type I collagen. ZOL reduced the mineral/matrix ratio and increased carbonate/phosphate ratio. It was observed a significant reduction on Wnt10b and beta-catenin immunolabeling in the bone tissue of ZOL group. Conclusion In summary, MRONJ model caused bone necrosis due to intense inflammation. Wnt signaling seems to play an important role in this process. Clinical relevance New therapeutic strategies focusing on Wnt pathway can provide an interesting approach for future treatments.