Since the late 1990s it has been known that the Sonic Hedgehog gene (Shh) controls tooth growth and morphogenesis (Dassule et al, 2000).
Shh is a thyroid-hormone (TH)-responsive gene.
Shh and Dental Fluorosis
Although fluoride and dental fluorosis (DF) have been studied for over 80 years, dental researchers claim that the mechanisms leading to DF are not yet known.
SEE: http://poisonfluoride.com/phpBB3/viewtopic.php?t=611
However, they declare the condition to be of "cosmetic concern" only.
For 20 years we have investigated the literature on this matter and have come to the conclusion that DF is caused by disturbances in thyroid hormone metabolism - that DF is a visual sign that TH metabolism and regulated pathways have been disturbed at a time crucial for development.
To further prove our case we have been looking all over the world for any research documenting the effects of fluoride on Shh, and specifically Shh involvement in DF.
We have been astounded by the fact that we could not find ANY scientific literature on Shh and DF in common medical literature databases, such as PUBMED, or SCIFinder.
It appeared that nobody had yet realized that this might be an important issue to investigate.
Today (thanks to Jirong) we found the first studies on the effects of fluoride on Shh in DF. They were found in the Chinese literature. Two papers on the subject had been published, one in 2007 and one in 2012.
As we had expected - the studies show that fluoride affects the expression of Shh.
Wendy
Shh & Dental Fluorosis
Chen L, Wang Y, Yang W, Tian M - "Effects of different selenium levels on tooth germ development in fluorosis rats" Journal of Oral Science Research 5:417-419, 422 (2012) PFPC Library
Liu H, Wang O, Zhu F, Luo PP, Liu TL, Wei XL, Wang LL - "Effect of fluorosis on the expression of Shh in rat incisors" Beijing Journal of Stomatology 15(4) (2007) PFPC LibraryTo study the effect of different selenium levels on dental germ development of rats with fluorosis, methods were employed as follows:
Methods: Sixty male SD rats are divided randomly into 6 groups. The control group is fed with a normal diet and distilled water. The experimental groups are fed with distilled water containing 45m/L fluoride (F−). The fluoride group is fed with a normal diet. The first fluorine and selenium group is fed with a diet containing 1.37mg/kg of selenium. The second fluorine and selenium group is fed with a diet containing 1.6mg/kg of selenium. The third fluorine and selenium group is fed with a diet containing 2.3mg/kg of selenium. The fourth fluorine and selenium group is fed with a diet containing 4mg/kg of selenium. At the end of the experiment, the rats were decapitated. Immunohistochemistry is used to detect the expression of smad3, shh in secretory ameloblasts.
Results: The expression of ameloblasts smad3 and shh is positive in the control group, and the expression in the fluoride group was significantly reduced compared with the control group. The fluorine and selenium groups' smad3 and shh expression were stronger than that of the fluoride groups, especially the third group is best.
Conclusion: The mechanism of the antagonizing effect of selenium with fluorosis may be related to the expression of the signal transduction factors smad3, shh, which control the dental germ development, and 2.3mg/kg selenium is best.
目的 研究过量氟对大鼠切牙Shh(Sonic Hedgehog)表达的影响,从分子水平探讨氟斑牙的发病机制.方法 20只Wistar大鼠随机分为2组:对照组(饮用蒸馏水)和实验组(饮用100 mg/L氟化水),复制氟斑牙动物模型,8周末处死动物,获取切牙标本,免疫组化染色观察Shh在大鼠切牙的表达定位及在对照组与实验组切牙表达的变化.结果 Shh在分泌期成釉细胞、成牙本质阳性表达.实验组Shh的表达明显弱于对照组,差异有显著性(P<.01).结论 过量氟可能通过抑制Shh的表达,从而影响牙齿发育的启动和随后的细胞分化,导致釉质发育障碍.
Objective To study the excessive fluoride on rat incisor Shh (Sonic Hedgehog) expression, from the molecular level investigate the pathogenesis of dental fluorosis. Methods 20 Wistar rats were randomly divided into two groups: control group (distilled water) and experimental group (drinking 100 mg / L fluoride water), copy dental fluorosis animal models, 8 weeks the animals were sacrificed to obtain incisor specimens, immunohistochemical staining of Shh expression in the rat incisor positioning and in the control group and the experimental group cut Teeth expression changes. Results Shh secretory ameloblasts in, odontoblasts expression. Shh expression in the experimental group was significantly weaker than the control group, the difference was statistically significant (P <.01). Conclusions Shh excessive fluoride may inhibit the expression, thus affecting tooth development startup and subsequent cell differentiation, leading to enamel developmental disorders.
SEE ALSO - smad3
Luo Pingping, Wang Qiang, Liu Hui - "Excessive fluoride during the development of rat incisor smad3 expression" Practical Stomatology, 3:377-379 (2007) PFPC Library
Shh & Thyroid Hormone | Deiodinase
Desouza LA, Sathanoori M, Kapoor R, Rajadhyaksha N, Gonzalez LE, Kottmann AH, Tole S, Vaidya VA - "Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult Mammalian brain" Endocrinology 152(5):1989-2000 (2011)
https://academic.oup.com/endo/article/1 ... 89/2457119
Dentice M - "Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases" Expert Opin Ther Targets 15(4):493-504 (2011)
https://www.tandfonline.com/doi/full/10 ... 011.553607
Dassule HR, Lewis P, Bei M, Maas R, McMahon AP - "Sonic hedgehog regulates growth and morphogenesis of the tooth" Development 127(22):4775-85 (2000)
http://dev.biologists.org/content/127/22/4775.long
Shh & Tooth Development
Zhang Lu, Sun Zhijun, Wang Zhifeng, Hua Fang, Zhang Qi, Chen Zhi - "Expression of Shh and Its Recepters mRNA in the Late Tooth Development of Murine Lower Incisor" Journal of Wuhan University: Medical Edition 4:419-421 (2004) PFPC Library
Gritli-Linde A, Bei M, Mass R,et al. - "Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization" Development 129(23):5323 (2002)Objective: To investigate the temporal and spatial expression of Shh and its receptors Ptc1、Ptc2 mRNA in the late tooth development of murine lower incisor and to discuss its role in cyto diff erentiation.Methods: The embryonic mouse mandibles of late incisor development(E18.5~P 1.5 ) were obtained and 5μm serial sections were made. DIG labeling RNA probes of Shh,Ptc1 and Ptc2 were generated by in vitro transcription from Shh、Ptc1、Ptc2 cDNA template. The expression pattern of Shh,Ptc1 and Ptc2 mRNA was analyzed by means of in situ hybridization. Results: The expression pattern of Shh and Ptc2 was similar. In the late tooth development,they were expressed in the inner dental epithelium and stratum intermedium of the incisor labial side. Ptc1 mRNA was expressed in the inner dental epithelium and stratum intermedium as well as the odontoblast. Conclusion: In the late incisor development,Shh might participate in the ameloblast and odontoblast differentiation as a paracrine or autocrine signaling molecule.
Hardcastle Z, Hui CC, Sharpe PT - "The Shh signalling pathway in early tooth development" Cell Mol Biol (Noisy-le-grand) 45(5):567-78 (1999) PMID: 10512189.
林媛;吴补领;陆群 Shh在大鼠牙胚发育过程中的表达 [期刊论文] -临床口腔医学杂志2004(04) doi:10.3969/j.issn.1003-1634.2004.04.004
陈智;张露;王志峰 Shh及其受体Ptc1、Ptc2在鼠帽状期磨牙的基因表达 [期刊论文] -中华口腔医学杂志2003(02)
杜娟;刘淑红;范文红 Sonic hedgehog在小鼠胚胎颌面部的表达 [期刊论文] -北京口腔医学2005(01)