Shh and fluoride

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Shh and fluoride

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August 20, 2013

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)-regulated 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.

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 med. 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 inhibits the expression of Shh.


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)

Dentice M - "Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases" Expert Opin Ther Targets 15(4):493-504 (2011)

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)

陈黎明, 王颖莉, 杨威, 田茂能 - 口腔医学研究, 2012

日前,贵阳市口腔医院口腔内科的陈黎明、王颖莉和杨威等研究人员共同发表论文,旨在研究不同硒水平对氟中毒大鼠牙胚发育的影响。该研究指出,硒拮抗氟中毒作用的机制可能与调控牙胚发育作用的信号转导因子Smad3和Shh的表达有一定的关联,且2.3 mg/kg硒效果最好。该文发表在2012年28卷05期《口腔医学研究》上。
  该研究的方法是,雄性SD大鼠60只,随机分为6组。对照组饮蒸馏水饲普通饲料,实验组饮含氟(F-)45 mg/L的蒸馏水,氟组饲普通饲料,氟硒1组饲含硒1.37 mg/kg的饲料,氟硒2组饲含硒1.6 mg/kg的饲料,氟硒3组饲含硒2.3 mg/kg的饲料,氟硒四组饲含硒4 mg/kg的饲料,饲养8周后断头处死大鼠,运用免疫组织化学检测技术检测smad3、shh在分泌期成釉细胞中的表达水平。

Recently, Guiyang City Dental Hospital Oral Medicine of Chen Liming, Yang Wei Wang Yingli and other researchers jointly published a paper aims to study different levels of selenium on fluorosis rat tooth development impact. The study pointed out that the role of selenium antagonism fluorosis may be related to regulation of tooth development role in signal transduction factors Smad3 and Shh expression have some relevance, and 2.3 mg / kg selenium best. This article was published in the 2012 Volume 28 05 "Oral Science Research" on.
  The research approach is 60 male SD rats were randomly divided into six groups. Control group fed normal diet drink distilled water, the experimental group drinking fluorinated (F-) 45 mg / L of distilled water, fluoride group fed with normal diet, fluorine, selenium and a group fed selenium 1.37 mg / kg of feed, feed containing fluorine, selenium group 2 Selenium 1.6 mg / kg feed, fluorine, selenium and selenium three groups fed 2.3 mg / kg feed, fluorine, selenium and selenium fed four groups of 4 mg / kg of feed, feeding rats were sacrificed after 8 weeks, the use of immunohistochemistry testing technology smad3, shh secretory ameloblasts in the expression level.
  The results of the study, the results of immunohistochemistry for the control rats ameloblasts smad3, shh expression is positive, fluorine rats ameloblasts smad3, shh expression was significantly decreased compared with the control group; fluorine, selenium group smad3, shh express stronger than fluoride group, in which three groups of fluorine, selenium best.

[8] 刘辉,王强,朱峰 . 过量氟对大鼠切牙shh表达的影响 . 北京口腔医学 , 2007年 15卷 第04期

过量氟对大鼠切牙Shh表达的影响 ... x200704008

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)

Tongji University Department of Oral Medicine
Kunshan, Jiangsu University Affiliated Hospital of Stomatology
Shanghai Stomatology Treatment Centers
East Hospital Affiliated to Tongji University, Department of Stomatology

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

[7] 罗平平,王强,刘辉 . 过量氟对大鼠切牙发育过程中smad3表达的影响 . 实用口腔医学杂志 , 2007年 23卷 第03期

[7] Luo Pingping, Wang Qiang, Liu Hui . excessive fluoride during the development of rat incisor smad3 expression of Practical Stomatology, 2007 Volume 23 03

The Shh signalling pathway in tooth development:defects in Gli2 and Gli3 mutants

(Its constitutive activation is associated with cancer development.)

Expression of Shh and Its Recepters mRNA in the Late Tooth Development of Murine Lower Incisor

Zhang Lu,Sun Zhijun,Wang Zhifeng,et alKey Laboratory for Oral Biomedical Engineering,School of Stomatology,Wuhan University,Wuhan 430079,China ... 404017.htm

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.
【Key Words】: signaling molecule gene expression mice tooth germ incisor
【Fund】: 国家自然科学基金资助项目 (3 0 1710 11)
【CateGory Index】: R78
The expression of Shh during rat teeth development

LIN Yuan, WU Bu-ling, LU Qun,JI Lan,HAN Hua.School of Stomatology,The Fourth Military Medical University,Xi'an 710032,China
Objective:To investigate the expression of Shh during rat teeth development.Method:We applied immunohistochemical techniques to examine the expression of Shh in rat teeth development at different stage. Result: Shh was expressed in all stage of tooth germ. Immunostaining for shh was detected in dental epithelium , oral epithelium, and ameloblasts. Shh was weakly expressed in odontoblasts.Conclusion: The expression of Shh has spatio-temporal characters, it may play a role in enamel and dentin formation.

Journal of Hubei Medical University》 2004-04 ... 404017.htm

TH regulates the expression of the Shh signaling pathway in the embryonic and adult Mammalian brain (Desouza et al, 2001).

Hardcastle Z; Hui CC; Sharpe PT The Shh signaling pathway in Early Tooth Development [foreign periodicals] 1999 (05)

Shh and tooth development:

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)

过量氟对大鼠切牙成釉细胞Cbfα1表达的影响 (2008) ... 01019.aspx

TGF-β1 in rat incisor fluorosis pulp Expression
TGF-β1在氟中毒大鼠切牙牙髓中的表达 (2006) ... 02020.aspx


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Sonic Hedgehog - SHH and T3

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Ostasov P, Tuma J, Pitule P, Moravec J, Houdek Z, Vozeh F, Kralickova M, Cendelin J, Babuska Vm - "Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells" Int J Mol Sci 21(10):3672 (2020)


Neural stem cells are fundamental to development of the central nervous system (CNS)-as well as its plasticity and regeneration-and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

Keywords: cell differentiation; embryonic neural stem cells; sonic hedgehog; triiodothyronine.
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Re: Shh and Gq/11

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Adachi C, Kakinuma N, Jo SH, Ishii T, Arai Y, Arai S, Kitaguchi T, Takeda S, Inoue T - "Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes" J Biol Chem 294(44):16034-16048 (2019) doi: 10.1074/jbc.RA119.007883. Epub 2019 Sep 10. PMID: 31506300; PMCID: PMC6827318.


Sonic hedgehog (SHH) is important for organogenesis during development. Recent studies have indicated that SHH is also involved in the proliferation and transformation of astrocytes to the reactive phenotype. However, the mechanisms underlying these are unknown. Involvement of SHH signaling in calcium (Ca) signaling has not been extensively studied. Here, we report that SHH and Smoothened agonist (SAG), an activator of the signaling receptor Smoothened (SMO) in the SHH pathway, activate Ca oscillations in cultured murine hippocampal astrocytes. The response was rapid, on a minute time scale, indicating a noncanonical pathway activity. Pertussis toxin blocked the SAG effect, indicating an involvement of a Gi coupled to SMO. Depletion of extracellular ATP by apyrase, an ATP-degrading enzyme, inhibited the SAG-mediated activation of Ca oscillations. These results indicate that SAG increases extracellular ATP levels by activating ATP release from astrocytes, resulting in Ca oscillation activation. We hypothesize that SHH activates SMO-coupled Gi in astrocytes, causing ATP release and activation of Gq/11-coupled P2 receptors on the same cell or surrounding astrocytes. Transcription factor activities are often modulated by Ca patterns; therefore, SHH signaling may trigger changes in astrocytes by activating Ca oscillations. This enhancement of Ca oscillations by SHH signaling may occur in astrocytes in the brain in vivo because we also observed it in hippocampal brain slices. In summary, SHH and SAG enhance Ca oscillations in hippocampal astrocytes, Gi mediates SAG-induced Ca oscillations downstream of SMO, and ATP-permeable channels may promote the ATP release that activates Ca oscillations in astrocytes.
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Re: Shh and fluoride

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ZHAO Li-na, YU Yan-ni, ZHU al, . Expressions of protein and mRNA relevant to hedgehog signaling pathway in liver of fluorosis rats[J]. Chinese Journal of Public Health, 2015, 31(9): 1162-1166. doi: 10.11847/zgggws2015-31-09-16
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