Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene-related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate.

中文翻译：

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感觉去神经支配通过降钙素基因相关肽和 P 物质的不成比例表达增加双膦酸盐诱导骨坏死的可能性

双膦酸盐相关的颌骨坏死 (BRONJ) 是系统给予双膦酸盐 (BPs) 的严重副作用。感觉神经支配对骨骼愈合至关重要。我们建立了下牙槽神经损伤（IANI）和下牙槽神经横断（IANT）模型，其特征是骨膜紊乱、破骨细胞增加和神经肽表达不平衡。唑来膦酸注射液通过降低降钙素基因相关肽 (CGRP) 和增加 P 物质 (SP) 来破坏 IANI 和 IANT 模型中神经肽的表达；与此相关的是，BRONJ 患病率在 IANT 模型中显着更高，其次是 IANI 模型和假对照。CGRP 治疗显着减少了 BRONJ 的发生，而 SP 给药具有相反的效果。体外，RAW 264。7个细胞用BPs处理，然后用CGRP和/或SP处理以研究唑来膦酸盐毒性的变化；CGRP 和 SP 的联合应用降低了唑来膦酸盐的毒性，而单独应用 CGRP 或 SP 没有显示出效果。这些结果表明，感觉去神经支配促进了 BRONJ 的发生，并且治疗上使用的 CGRP 可以防止 BRONJ 进展，前提是 SP 也存在。需要进一步的研究来确定 CGRP 与 SP 促进骨愈合的最佳比例，并揭示 CGRP 和 SP 合作的机制。这些结果表明，感觉去神经支配促进了 BRONJ 的发生，并且治疗上使用的 CGRP 可以防止 BRONJ 进展，前提是 SP 也存在。需要进一步的研究来确定 CGRP 与 SP 促进骨愈合的最佳比例，并揭示 CGRP 和 SP 合作的机制。这些结果表明，感觉去神经支配促进了 BRONJ 的发生，并且治疗上使用的 CGRP 可以防止 BRONJ 进展，前提是 SP 也存在。需要进一步的研究来确定 CGRP 与 SP 促进骨愈合的最佳比例，并揭示 CGRP 和 SP 合作的机制。