Sarram S, Lee K F, Byers M R
Department of Endodontics, University of Washington, Seattle 98195-6540, USA.
J Comp Neurol. 1997 Aug 25;385(2):297-308. doi: 10.1002/(sici)1096-9861(19970825)385:2<297::aid-cne8>3.0.co;2-x.
Adult dental tissues have unusual neurotrophin biology. Pulpal fibroblasts express nerve growth factor (NGF) and the low-affinity p75 neurotrophin receptor, their sensory nerve fibers express p75 and trk A, and pulpal sympathetic fibers lack p75. Following tooth injury, there is increased pulpal NGF, sprouting of sensory nerve endings, and increased immunoreactivity for the sensory neuropeptide calcitonin gene-related peptide (CGRP). In the present study, we have analyzed tooth structure and innervation of pulp and periodontal ligament in young (6-8 weeks, 3 months) and older (5-12 months) adult mice carrying a null mutation in the p75 gene and compared the results with those of age-matched wild-type controls. Our hypotheses were that tooth structure would be abnormal and that pulpal innervation would be greatly reduced because it consists primarily of nociceptive fibers that have been found to be severely depleted in skin of p75(-/-) mice. Tissues were fixed, X-rayed for gross dental morphology, decalcified, and analyzed for immunoreactivity for CGRP and for a general nerve marker, protein gene product 9.5. Radiographs showed worn-down molar crowns in p75-deficient mice. Light microscopy confirmed the accelerated molar wear and showed intense CGRP immunoreactivity in pulp nerve endings of mutant mice, compared with a gradual decrease in CGRP intensity in controls during normal aging. The CGRP intensity in 5-12-month-old pairs of mice was threefold greater in the mutants (P < 0.03), and in younger mice the mutant always had more CGRP than its matched control. The innervation of molar ligament in all p75-deficient mice was similar to that of controls except there was nerve sprouting near bone loss in mutants. The incisors of mutant mice did not have unusual wear and their pulpal CGRP immunoreactivity remained normal, but their periodontal ligament had fewer thin branched nerve endings at all ages. Thus, most innervation of teeth and their supporting tissues developed normally, and the only neural changes in p75(-/-) mutant mice were the reduction of incisor ligament sensory receptors and increased molar CGRP. Sensory nerves in teeth gradually lose neuropeptide intensity during aging, but that did not happen in the mutant mice, suggesting that the accelerated molar wear stimulated persistent high levels of CGRP.
成年牙齿组织具有独特的神经营养因子生物学特性。牙髓成纤维细胞表达神经生长因子（NGF）和低亲和力p75神经营养因子受体，其感觉神经纤维表达p75和trk A，而牙髓交感神经纤维缺乏p75。牙齿损伤后，牙髓NGF增加，感觉神经末梢发芽，感觉神经肽降钙素基因相关肽（CGRP）的免疫反应性增强。在本研究中，我们分析了携带p75基因无效突变的年轻（6 - 8周、3个月）和老年（5 - 12个月）成年小鼠的牙齿结构以及牙髓和牙周韧带的神经支配情况，并将结果与年龄匹配的野生型对照进行比较。我们的假设是牙齿结构会异常，并且牙髓神经支配会大大减少，因为它主要由伤害性纤维组成，而在p75（-/-）小鼠的皮肤中已发现这些纤维严重减少。组织经固定、X射线检查牙齿大体形态、脱钙，并分析CGRP和一般神经标志物蛋白基因产物9.5的免疫反应性。X线片显示p75缺陷小鼠的磨牙牙冠磨损。光镜证实磨牙磨损加速，并显示突变小鼠牙髓神经末梢中CGRP免疫反应性强烈，而正常衰老过程中对照组CGRP强度逐渐降低。在5 - 12个月大的小鼠对中，突变体的CGRP强度比对照组高两倍（P < 0.03），在年轻小鼠中，突变体的CGRP总是比其匹配的对照多。除了突变体在骨质流失附近有神经发芽外，所有p75缺陷小鼠的磨牙韧带神经支配与对照组相似。突变小鼠的切牙没有异常磨损，其牙髓CGRP免疫反应性保持正常，但在所有年龄段其牙周韧带的细分支神经末梢较少。因此，牙齿及其支持组织的大多数神经支配正常发育，p75（-/-）突变小鼠唯一的神经变化是切牙韧带感觉受体减少和磨牙CGRP增加。牙齿中的感觉神经在衰老过程中逐渐失去神经肽强度，但在突变小鼠中并未发生这种情况，这表明加速的磨牙磨损刺激了CGRP的持续高水平。
