Draft:Original research/Human teeth

Teeth of humans are small, calcified, hard, whitish structures found in the mouth. They function in mastication mechanically breaking down items of food by cutting and crushing them in preparation for swallowing and digestion. The roots of teeth are embedded in the maxilla (upper jaw) or the mandible (lower jaw) and are covered by gingiva gums. Teeth are made of multiple tissues of varying density and hardness.

Theory of teeth
Def. a "hard, calcareous structure present in the mouth of many vertebrate animals, generally used for eating" is called a tooth.

The image on the right is a model of a human molar-like tooth. Its components are labeled:


 * 1) Tooth:
 * 2) Enamel
 * 3) Dentin
 * 4) Dental pulp:
 * 5) cameral pulp
 * 6) root pulp
 * 7) Cementum
 * 8) Crown
 * 9) Cusp
 * 10) Sulcus
 * 11) Cementoenamel junction or Neck
 * 12) Root
 * 13) Furcation
 * 14) Root apex
 * 15) Apical foramen
 * 16) Gingival sulcus
 * 17) Periodontium:
 * 18) Gingiva:
 * 19) free or interdental
 * 20) marginal
 * 21) alveolar
 * 22) Periodontal ligament
 * 23) Alveolar bone
 * 24) Vessels and nerves:
 * 25) dental
 * 26) periodontal
 * 27) alveolar through alveolar canals.

Genetics
Genetics involves the identification, expression, transmission, and variation of inherited characteristics.

Def. a "branch of biology that deals with the transmission and variation of inherited characteristics, in particular chromosomes and DNA" is called genetics.

Objects
Def. the "hard covering on the exposed part of a tooth" is called the enamel.

Def. the "hard, dense calcareous material that makes up the bulk of a tooth" is called the dentin.

Def. the "soft center of a tooth" is called the pulp.

Liquid objects
"Pulp cells from human permanent molars were isolated and established in culture; 40% showed positive alkaline phosphatase staining."

The "cells formed a mineralized extracellular matrix; they could thus have the potential to differentiate into odontoblast-like cells in vitro."

The "cells produced predominantly (~99%) type I collagen and only trace amount of type III collagen. The ratio of α1(I) to α2(I) procollagen chains was about 68:32, indicating that no significant amount of collagen type I trimer was synthesized in this system. The ratios of α1(I), α2(I) and α1(III) procollagen mRNAs were about 61:25:1; these were compatible with the ratios of corresponding procollagen a chains. In addition, a novel 5.8 kb proα1(III) mRNA was detected. These observations indicate that collagen synthesis in these cultured pulp cells was regulated at the transcriptional level."

GeneID: 765 carbonic anhydrase 6 [ Homo sapiens (human) ].

"We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) of the carbonic anhydrase VI was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918)."

"The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility."

GeneID: 3479 IGF1 insulin like growth factor 1 [ Homo sapiens (human) ].

"The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein."

GeneID: 3480 IGF1R insulin like growth factor 1 receptor [ Homo sapiens (human) ].

"IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1."

"The teeth [showing ongoing development] showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. [...] members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation."

GeneID: 7124 TNF tumor necrosis factor [ Homo sapiens (human) ].

"Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown."

"TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis."

"Various signaling pathways [image on the right], such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways."

The "differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway."

Bones
GeneID: 860 RUNX2 runt-related transcription factor 2 [ Homo sapiens (human) ].

"This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing."

"Cleidocranial dysplasia (CCD) is characterized by the runt-related transcription factor 2 (RUNX2) mutation, which results in delayed tooth eruption due to disturbed functions of dental follicle. Accumulating evidence has revealed a key regulatory circuit, including RUNX2, miR-31, and special AT-rich binding protein 2 (SATB2) acting in concert in mesenchymal stem cell homeostasis and functions. However, whether such a regulatory loop works in dental follicle cells (DFCs) remains unknown."

A "novel mutation on exon 5 (c.634T>G, p.T212P) in RUNX2 via exome sequencing in the [cleidocranial dysplasia] CCD patient [has] typical clinical presentations."

"Compared with [dental follicle cells] DFCs from healthy donors, DFCs-CCD displayed significantly lower osteogenic, osteoclast-inductive, and matrix-degrading capacities and had lower RUNX2 (a transcriptional inhibitor of miR-31), higher miR-31, and downregulated [special AT-rich binding protein 2] SATB2. Lower ratios of RANKL/OPG and RANKL/RANK, as well as decreased expression of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2), would lead to inactivation of osteoclasts and suppression of bone matrix remodeling in DFCs-CCD. Furthermore, the roles of the RUNX2-miR-31-SATB2 loop in DFCs-CCD were revealed by endogenous miR-31 knockdown, which resulted in increased SATB2 and RUNX2, as well as osteoclast-inductive and matrix degradation capacities. Conversely, SATB2, RUNX2, MMP9, MMP2, and osteoclast-inductive factors expression declined upon ectopic miR-31 overexpression in normal DFCs. Importantly, neonatal mice with in vivo siRUNX2 delivery exhibited less activated osteoclasts around dental follicles and delayed tooth eruption."

GeneID: 1277 COL1A1 collagen, type I, alpha 1 [ Homo sapiens (human) ].

"This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. [...] Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene."

Matrix metalloproteinases
"Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes capable of degrading most components of the extracellular matrix."

"MMPs may play a role in tissue degradation in inflamed dental pulp."

Gene ID: 4313 MMP2 matrix metallopeptidase 2 [ Homo sapiens (human) ].

"The main gelatinase secreted by human pulp and [periodontal ligament] PDL cells migrated at 72 kDa and represented MMP-2."

Gene ID: 4318 MMP9 matrix metallopeptidase 9 [ Homo sapiens (human) ].

"Minor gelatinolytic bands were also observed at 92 kDa regions that correspond to MMP-9."

Alkaline phosphatases
GeneID: 249 ALPL alkaline phosphatase, liver/bone/kidney [ Homo sapiens (human) ].

ALPL is an alkaline phosphatase, liver/bone/kidney in humans. "The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization; however, mice that lack a functional form of this enzyme show normal skeletal development. This enzyme has been linked directly to hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation since this determines age of onset and severity of symptoms." Bold added.

"Mutations in hypophosphatasia reduce the function of tissue nonspecific alkaline phosphatase, and the resulting increase in pyrophosphate contributes to bone and tooth mineralization defects by inhibiting physiologic calcium-phosphate precipitation."

"Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (Pi) to mineral inhibitor pyrophosphate (PPi), where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)."

"TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected."

Transcription factors
GeneID: 860 RUNX2 runt-related transcription factor 2 [ Homo sapiens (human) ].

RUNX2 "is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD)."

RUNX2 is involved in "odontogenesis of [any] dentin-containing tooth [and] regulation of odontogenesis of [any] dentin-containing tooth".

Homeoboxes
GeneID: 4487 MSX1 msh homeobox 1 [ Homo sapiens (human) ].

MSX1 "encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia."

"Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family. ... [T]he nonsense mutation in MSX1 might have resulted in rapid degradation of the mutated transcript and caused the phenotype of tooth agenesis with cleft lip in the Chinese family."

"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."

MSX1 is involved in "odontogenesis of [any] dentin-containing tooth".

Gene ID: 5083 PAX9 paired box 9 [ Homo sapiens (human) ].

"This gene is a member of the paired box (PAX) family of transcription factors."

"Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3."

"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."

Tachykinin peptide hormones
GeneID: 6863 TAC1 tachykinin precursor 1 [ Homo sapiens (human) ].

TAC1 tachykinin, precursor 1 "encodes four products of the tachykinin peptide hormone family, substance P and neurokinin A, as well as the related peptides, neuropeptide K and neuropeptide gamma. These hormones are thought to function as neurotransmitters which interact with nerve receptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Multiple transcript variants encoding different isoforms have been found for this gene."

"Transcript variant beta encodes the full-length form of this gene. It encodes hormones substance P, neurokinin A, as well as the neuropeptide K."

"As compared to the full-length transcript variant beta, variant alpha lacks exon 6, and therefore does not encode neuropeptide K, neurokinin A, or neuropeptide gamma. This transcript does encode the hormone substance P located on exon 3."

"As compared to the full-length transcript variant beta, variant gamma lacks exon 4, and therefore does not encode neuropeptide K. This transcript does encode substance P, neurokinin A, and is the only variant that encodes neuropeptide gamma."

"As compared to the full-length transcript variant beta, variant delta lacks both exons 4 and 6; therefore, it does not encode neurokinin A, neuropeptide K, or neuropeptide gamma. It does encode the hormone substance P located on exon 3."

Notation: let CGRP stand for Calcitonin Gene-Related Peptide.

Notation: let NKA represent neurokinin A.

"Substance P and CGRP [are] present in [painful and healthy pulp tissue from human adult teeth] and NKA [is] detected in 96% of the pulps. CGRP [is] present in much higher concentrations than SP and NKA in both painful and non-painful teeth. The painful teeth had significantly higher concentrations of SP ..., NKA ... and CGRP ... than non-painful teeth. The concentration of CGRP [are] significantly higher in the pulps of smokers compared with non-smokers ...."

Gene transcriptions
GeneID: 8091 HMGA2 high mobility group AT-hook 2 [ Homo sapiens (human) ].

A genome-wide "association study identifies four loci [of GeneID: 8091 HMGA2 high mobility group AT-hook 2] associated with eruption of permanent teeth."

Hypotheses

 * 1) When the genome within each tooth is properly signaled, it will begin to heal the tooth from the inside out against caries and any other illness of the teeth.