Lactoferrin: A Roadmap to the Borderland between Caries and Periodontal Diseaseby D. H. Fine

Journal of Dental Research


Dentistry (all)



Journal of Dental Research 1 –9 © International & American Associations for Dental Research 2015

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DOI: 10.1177/0022034515577413

Critical Reviews in Oral Biology & Medicine


Saliva continuously bathes oral tissues and can be considered the biofluid that sustains structural integrity in the oral cavity.

On a daily basis, salivary glands produce approximately 1 to 1.5 L of saliva (Scannapieco 1994). Reduced salivary flow can have severe consequences (Mandel 1987). For example, patients with irradiated salivary glands have excessive caries and dry, leather-like cracking mucosa on the same side as the irradiated gland (Dreizen and Brown 1976). The importance of saliva has been highlighted in healthy subjects as well. Studies have shown that saliva modulates the interaction between the bacterial flora and oral tissues by means of its buffering capacity, ability to dilute and wash away substances that can antagonize oral tissues, and healing capabilities by supplying calcium to compromised enamel surfaces (Mandel 1987; Scannapieco 1994). In addition, saliva possesses a potent combination of antimicrobial factors that could affect bacteria, viruses, and fungi capable of attacking oral tissues (Sikorska et al. 2002).

While several salivary components have been shown to possess attributes that can affect oral stability and modify dental disease, characterization of genetic variations in specific salivary proteins and the effect of these variants on oral disease outcomes have been slow to materialize (Helmerhorst and

Oppenheim 2007). The focus of this review is on lactoferrin and its potential to affect both caries and periodontal disease.

Special emphasis in this review is placed on genetic polymorphisms that exist in the antibacterial region of lactoferrin and the potential of these variants to influence the presentation of dental disease.


A Ubiquitous Biodiverse Molecule

Lactoferrin is typically found in saliva at concentrations of 1 to 7 µg/mL (Scannapieco 1994). It is also found in crevice fluid (Friedman et al. 1983). In addition to its “ubiquitous” presence, 577413 JDRXXX10.1177/0022034515577413Journal of Dental ResearchLactoferrin: A Roadmap research-article2015 1Department of Oral Biology, Rutgers School of Dental Medicine,

Rutgers University, Newark, NJ, USA

A supplemental appendix to this article is published electronically only at

Corresponding Author:

D.H. Fine, Department of Oral Biology, Rutgers School of Dental

Medicine, Rutgers University, Medical Science Building, C-636, Newark,

NJ, 07103 USA.


Lactoferrin: A Roadmap to the

Borderland between Caries and

Periodontal Disease

D.H. Fine1


Lactoferrin is one of a number of multifunctional proteins that are present in or on all mucosal surfaces throughout the body. Levels of lactoferrin are consistently elevated in inflammatory diseases such as arthritis, inflammatory bowel diseases, corneal disease, and periodontitis. Single-nucleotide polymorphisms (SNPs) in lactoferrin have been shown to be present in individuals susceptible to

Escherichia coli–induced travelers’ diarrhea and in tear fluid derived from virally associated corneal disease. Here, we review data showing a lactoferrin SNP in amino acid position 29 in the antimicrobial region of lactoferrin that acts against caries associated bacteria. This

SNP was initially discovered in African American subjects with localized aggressive periodontitis (LAP) who had proximal bone loss but minimal proximal caries. Results were confirmed in a genetic association study of children from Brazil with this same SNP who showed a reduced level of caries. In vitro data indicate that lactoferrin from whole saliva derived from subjects with this SNP, recombinant human lactoferrin containing this SNP, or an 11-mer peptide designed for this SNP kills mutans streptococci associated with caries by >1 log. In contrast, the SNP has minimal effect on Gram-negative species associated with periodontitis. Moreover, periodontally healthy subjects homozygous for this lysine (K) SNP have lactoferrin in their saliva that kills mutans streptococci and have reduced proximal decay. The review summarizes data supporting the ecologic plaque hypothesis and suggests that a genetic variant in lactoferrin with K in position 29 when found in saliva and crevice fluid can influence community biofilm composition. We propose that, for caries, this SNP is ethnicity independent and protective by directly killing caries-provoking bacteria (reducing proximal decay). However, the clinical effect of this

SNP in LAP is ethnicity dependent, destructive (increases LAP incidence), and complex with mechanisms still to be determined.

Keywords: dental caries, aggressive periodontitis, single nucleotide polymorphisms, streptococcus mutans, saliva, ecosystem at Bobst Library, New York University on April 26, 2015 For personal use only. No other uses without permission.jdr.sagepub.comDownloaded from © International & American Associations for Dental Research 2015 2 Journal of Dental Research lactoferrin has been shown to have antimicrobial, antiviral, antifungal, anti-inflammatory, and anticancer properties (Farnaud and Evans 2003). Lactoferrin does not stand alone in its multifunctionality; however, its unique capability of binding iron has led to its characterization as a “metal iron chelator” (Gorr and Abdolhosseini 2011). Initially, lactoferrin was thought to have an indirect role in host defense because of its ability to sequester iron needed for bacterial survival. This bacteriostatic mechanism was thought to be lactoferrin’s primary function until it was demonstrated that iron-free lactoferrin had bactericidal activity that was independent of iron binding (Arnold et al. 1977; Arnold et al. 1981). Lactoferrin can also be viewed as a host defense protein that operates predominantly in the innate arm of the immune system, but it also affects adaptive immunity (Legrand et al. 2005, 2006).