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	A mutation in the ORAI1 gene-studied in a human patient and mice-leads to a loss of calcium in enamel cells and results in defective dental enamel mineralization, according to a study led by researchers at NYU College of Dentistry.

, identifies ORAI1 as the dominant protein for calcium influx and reveals the mechanisms by which calcium influx affects enamel cell function and the formation of tooth enamel.

	Calcium is critical for many cellular functions, including mineralizing teeth and bones. Calcium enters cells via ORAI proteins, which form pores in a cell’s plasma membrane to enable calcium influx when activated.

	"Our previous research has shown that deficiencies in the modulation of calcium influx or calcium transport result in dental enamel malformation,” says Rodrigo Lacruz, Ph.D., associate professor of basic science and craniofacial biology at NYU College of Dentistry and the study’s senior author. “Despite this knowledge, the biology of enamel cells as it relates to the role of calcium signaling remains poorly understood.”

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	Studies show that several genes, including ORAI (which encode ORAI proteins), are involved in the formation of tooth enamel. Enamel-the hard, outer layer of teeth-first forms as a soft, gel-like matrix. ORAI proteins then help the enamel-forming cells to mineralize.

	Mutations in the human ORAI1 gene result in immune dysfunction and immune diseases, but people with ORAI1 mutations also have defects in their tooth enamel. In this study, the researchers investigated the case of a patient with a complex medical history, including combined immunodeficiency and a mutation in the ORAI1 gene. Throughout his childhood, the patient had defects on his tooth enamel, resulting in severe cavities and related dental abscesses. Based on his clinical presentation, the researchers concluded that the ORAI1 mutation likely accounted for the defective enamel mineralization.

Given the lack of dental samples from patients with ORAI1 mutations, Lacruz and his colleagues then developed mouse models to study the role of ORAI proteins in enamel formation, both by observing tooth enamel and examining its influence on the environment inside enamel cells.

	The researchers studied the ORAI family of proteins (ORAI1, ORAI2 and ORAI3) and genetic mutations in the corresponding genes to investigate the mechanism by which calcium is modulated by each of these proteins. When mice had a mutation in the ORAI1 gene and were therefore deficient in ORAI1 protein, calcium entry into enamel cells was significantly reduced (by roughly 50 percent), and tooth enamel was abnormal, including cracks in the outer enamel layer. By contrast, mice with ORAI2 mutations and ORAI2 deficiency showed an increase in calcium by approximately 30 percent in the enamel cells, which did not result in obvious enamel defects. This suggests that ORAI1 is the dominant channel for modulating the influx of calcium into enamel cells.

	To better understand how calcium influx-and conversely, deficiency in calcium-changes the functioning of enamel cells, the researchers examined the activity of cells lacking ORAI1. They found that calcium dysregulation in ORAI1-deficient cells affects their function at multiple levels, including increased mitochondrial respiration and subsequent changes in redox balance. An elevation in reactive oxygen species can be detrimental to cells, and to protect proteins in an intracellular environment that is more oxidizing, a mechanism called S-glutathionylation is promoted.

	The findings provide a foundational understanding of what happens in enamel cells, which could help create a pathway for researchers interested in regenerating tooth enamel or developing therapies to treat patients with enamel defects.

	“We’ve long observed deficiencies in tooth enamel associated with abnormal calcium levels in the enamel cells but can now detail a mechanism for how this occurs,” Lacruz says.

	In addition to Lacruz, study authors include Miriam Eckstein, Francisco Aulestia, Veronica Costiniti, Serena Kassam, Timothy Bromage, and Amr Moursi of NYU College of Dentistry; Martin Vaeth and Stefan Feske of NYU School of Medicine; Pal Pedersen of Carl Zeiss Microscopy, LLC; Youssef Idaghdour of NYU Abu Dhabi; and Thomas Issekutz of Dalhousie University. This research was funded by the National Institutes of Health’s National Institute of Dental and Craniofacial Research (DE025639, DE027679) and National Institute of Allergy and Infectious Diseases (AI097302, AI130143, AI107448).

	To read the full study, titled "Differential regulation of Ca

 influx by ORAI channels mediates enamel mineralization," 

Articles

The findings could help to create a pathway for researchers interested in regenerating tooth enamel.

Study finds calcium deficiency due to gene mutation leads to damaged tooth enamel

	School-based prevention programs can substantially reduce children’s cavities - but what type of treatment should be delivered in schools to best prevent tooth decay?

	A new study by researchers at NYU College of Dentistry, 

, suggests that cavity prevention programs with a combination of prevention strategies may be more effective than one alone for reducing tooth decay.

	Dental cavities are the world’s most prevalent childhood disease, affecting nearly 30 percent of school-age children and 50 percent of rural, minority, or Medicaid-receiving children in the United States.

	School-based cavity prevention programs have emerged as an important way to improve access to dental services.  In medically underserved areas, these programs often serve as the sole source of dental care for children. While the 

 supports the use of school-based cavity prevention programs, questions remain on the optimal mix of treatment services, intensity, and frequency of care.

	“Given the high variability in school-based programs to prevent cavities, comparing the effectiveness of different prevention agents, frequency of care, or intensity of treatment can lead to optimal program design,” says 

., assistant professor of epidemiology and health promotion at NYU Dentistry and the study’s lead author.

	In this study, NYU Dentistry researchers compared two cavity prevention programs in elementary schools serving more than 8,200 students over 10 years (2004-2014). Both programs provided school-based care twice a year to children ages 5 to 12.

	One program provided sealants on molars (primary prevention) while the other provided sealants on all teeth and interim therapeutic restorations (primary and secondary prevention). Interim therapeutic restorations are a minimally-invasive method for controlling tooth decay by filling a cavity with a fluoride-releasing agent. Interim therapeutic restorations are intended to bridge the gap between identifying a cavity, particularly in a nontraditional setting or in a very young child, and having the cavity filled or crowned in a more permanent procedure.

Both school-based cavity prevention programs reduced the risk of untreated decay over time. While the total number of all decayed or filled teeth observed over the course of the study increased across both programs, the comprehensive program that provided primary and secondary prevention significantly lowered the rate of new and untreated cavities when compared to only sealants on molars.

	“A comprehensive cavity prevention program, particularly for children without regular access to dental care, can be significantly better than the traditional molar sealant programs,” says 

, professor and chair of the department of epidemiology and health promotion at NYU Dentistry and the study’s co-author.

	Ruff and Niederman are continuing to study how to optimize school-based cavity prevention. They are currently leading two large studies – a PCORI-funded study in the Bronx and an NIH-funded study in New Hampshire – to compare two cavity prevention techniques in school-based dental programs. One technique is a more complex treatment similar to the combined primary and secondary prevention, but the Bronx and New Hampshire studies will also introduce the use of silver diamine fluoride, a noninvasive, cavity-fighting liquid that is painted onto teeth to halt the progression of tooth decay. The cavity prevention programs will begin in schools in the fall of 2018.

National Institute of Dental and Craniofacial Research

National Institute on Minority Health and Health Disparities

A combination of prevention strategies may be more effective than one alone for reducing tooth decay, according to researchers.