Periosteal microcirculatory reactions in a zoledronate-induced osteonecrosis model of the jaw in rats
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Nitrogen-containing bisphosphonates induce osteonecrosis mostly in the jaw and less frequently in other bones. Because of the crucial role of periosteal perfusion in bone repair, we investigated zoledronate-induced microcirculatory reactions in the mandibular periosteum in comparison with those in the tibia in a clinically relevant model of bisphosphonate-induced medication-related osteonecrosis of the jaw (MRONJ).
Materials and methods
Sprague–Dawley rats were treated with zoledronate (ZOL; 80 i.v. μg/kg/week over 8 weeks) or saline vehicle. The first two right mandibular molar teeth were extracted after 3 weeks. Various systemic and local (periosteal) microcirculatory inflammatory parameters were examined by intravital videomicroscopy after 9 weeks.
Gingival healing disorders (∼100 %) and MRONJ developed in 70 % of ZOL-treated cases but not after saline (shown by micro-CT). ZOL induced significantly higher degrees of periosteal leukocyte rolling and adhesion in the mandibular postcapillary venules (at both extraction and intact sites) than at the tibia. Leukocyte NADPH-oxidase activity was reduced; leukocyte CD11b and plasma TNF-alpha levels were unchanged.
Chronic ZOL treatment causes a distinct microcirculatory inflammatory reaction in the mandibular periosteum but not in the tibia. The local reaction in the absence of augmented systemic leukocyte inflammatory activity suggests that topically different, endothelium-specific changes may play a critical role in the pathogenesis of MRONJ.
This model permits for the first time to explore the microvascular processes in the mandibular periosteum after chronic ZOL treatment. This approach may contribute to a better understanding of the pathomechanism and the development of strategies to counteract bisphosphonate-induced side effects.
KeywordsMandibular periosteum Intravital fluorescence videomicroscopy Leukocytes Inflammation Bisphosphonate Osteonecrosis
This publication is supported by the European Union and co-funded by the European Social Fund. Research grants: TÁMOP 4.2.4. A/2-11-1-2012-0001 “National Excellence Program—Elaborating and operating an inland student and researcher personal support system convergence program;” TÁMOP 4.2.1/B-09/1/KONV-2010-0005; TÁMOP 4.2.2A-11/1/KONV-2012-0035; TÁMOP 4.2.2A-11/1/KONV-2012-0073 “Telemedicine-focused research activities on the field of Mathematics, Informatics and Medical sciences,” and OTKA 109388.
Conflict of interest
The authors declare that they have no conflict of interest.
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