Editorial Development, Disease, and Regeneration of Tissues ...periodontal disease can be...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 836871, 3 pageshttp://dx.doi.org/10.1155/2013/836871

EditorialDevelopment, Disease, and Regeneration of Tissues inthe Dental-Craniofacial Complex

Brian L. Foster,1 Yong-Hee P. Chun,2 Erica L. Scheller,3 Zhao Lin,4

Chad M. Novince,5 and Avina Paranjpe6

1 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH),9000 Rockville Pike Building 50, Room 4120, Bethesda, MD 20892, USA

2Department of Periodontics, University of Texas Health Science Center at San Antonio, TX 78229, USA3Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA4Department of Periodontics, Virginia Commonwealth University School of Dentistry, Richmond, VA 23298, USA5Department of Periodontics, University of Washington School of Dentistry, Seattle, WA 98195, USA6Department of Endodontics, University of Washington School of Dentistry, Seattle, WA 98195, USA

Correspondence should be addressed to Brian L. Foster; [email protected]

Received 25 July 2013; Accepted 25 July 2013

Copyright © 2013 Brian L. Foster et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

This special issue of BioMed Research International focuseson the theme of development, disease, and regenerationof tissues in the dental-craniofacial complex, highlightingdynamic research thatmakes this an exciting area of biomedi-cal research. Dental and craniofacial diseases have significantimplications for the oral and systemic health of the generalpublic. The dental-craniofacial tissues, more than any othertissue and organ of the body, are key for communicationand mastication. We are delighted to present in this specialissue of biomed research international a glimpse into diseasesof dental and craniofacial tissues, biology in development,and therapeutic innovations. The theme was chosen in orderto include fundamental basic science research highlightingnormal developmental processes and cases where these goawry (including disease models), as well as translational andclinical papers investigating therapeutic strategies for repairand regeneration of tissues. The aim of this introduction is tohighlight central concepts of the 11 individual papers undereach theme and further illuminate topics to be found in thepapers and throughout the special issue.

2. Disease

Diseases of the dental-craniofacial complex include a broadspectrum of illnesses, ranging from rare hereditary condi-tions to some of the most prevalent pathologies in the world,

including periodontal disease and premature tooth loss.Osteogenesis imperfecta (OI) is a rare inherited skeletaldisorder associated with defective collagen structure, pro-duction, or processing. Dental defects arising as a result ofOI represent one form of dentinogenesis imperfecta (DGI),which include reduced and defective dentin mineralization,alterations in tooth crown and root formation, and predis-position to tooth fractures and abscesses. In their report,A. Boskey et al. employed the Brtl/+ Gly349Cys knock-in mouse as a model for type IV OI, adopting an arrayof imaging techniques, including the Fourier transformedinfrared microscopic imaging (FTIRI), scanning electronmicroscopy (SEM), andmicrocomputed tomography (micro-CT) to elucidate the etiology of dentin defects in this mouse.The authors report reduced mineralized dentin volume inmolars of the knock-in mice, without changes in enamel.The expected alterations in collagen structure were observedat two months of age but self-corrected by six months.FTIRI identified increased acid phosphate content at bothages in knock-in mice, implying dentin matrix mineral-ization defects. These results indicate an impaired matrixmineralization and a slower correction of the phenotypewith age, implying that both the collagen matrix and thenoncollagenous proteins that regulate the function of thatmatrix may be altered in the Brtl/+ teeth and shedding lighton pathological mechanisms involved in tooth defects inpatients with DGI.

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Nonsyndromic DGI is caused by mutations in the dentinsialophosphoprotein (DSPP) gene. DSPP encodes for a largeprecursor protein that is cleaved into dentin sialoprotein(DSP) and dentin phosphoprotein (DPP), two prominentextracellularmatrix components involvedwith dentinminer-alization. In their paper, “A DSPP mutation causing dentino-genesis imperfecta and characterization of the mutationaleffect,” S. K. Lee et al. identified a mutation in exon 2 of DSPPin association with type III DGI in a Korean family. The DGIphenotype was quite severe, featuring tooth discoloration,severe attrition, and periapical inflammation.Throughmuta-tional analysis and in vitro assays, the authors report that theDSPPmutation resulted in retention of the mutant protein inthe endoplasmic reticulum, leading to defective secretion ofDSP.The samemutation was also found recently in a Chinesefamily and, interestingly, alters the same propeptide cleavagesite mutated in the classic Brandywine isolate of type III DGI,adding to genotype-phenotype understanding of DGI andother diseases affecting dentin formation andmineralization.

Craniosynostosis is a condition in which prematurefusion of cranial bones leads to elevated intracranial pressureand dysmorphic cranial and facial shapes. Repeated surgicalintervention is typically required to manage the associatedmorbidity and negative effects on quality of life.The Crouzonsyndrome, associated with gain-of-function mutations infibroblast growth factor receptor 2 (FGFr2), features cran-iosynostosis. The mechanism of its development remainsincompletely understood. J. Liu et al. studied the 𝐹𝑔𝑓𝑟2C342Ymouse model of the Crouzon syndrome, documenting thatprimary osteoblasts from the Crouzon mice feature elevatedexpression of early osteoblast markers, but reduced alkalinephosphatase and late osteoblast markers, and inhibition ofmineralization in 2D and 3D cultures. They also report, forthe first time, defective long bone formation in 𝐹𝑔𝑓𝑟2C342Yanimals. Their findings suggest that development of the axialand appendicular skeleton in 𝐹𝑔𝑓𝑟2C342Y mice is impaireddue to cell autonomous defects in the osteoblast.

Periodontal disease, affecting the tooth root cementum,periodontal ligament, and surrounding alveolar bone, affectsalmost 50% of US adults and, worldwide, is the mostprevalent cause of premature tooth loss. Despite numerousanimal models focusing on periodontal disease progression,few studies have assessed the role of functional mechanicsof the bone-PDL-tooth joint in disease progression. J. Leeet al. take this approach by employing a lipopolysaccharidesoaked ligature induced ratmodel of periodontal disease.Theauthors mapped two trends in response to disease induction.First, inflammation-induced degeneration of more coronalroot tissues and, second, mechanobiological changes in theapical periodontal regions, potentially resulting from coronaldegeneration over time. Interestingly, the authors noted thatcoronal induction of inflammation by ligature placementaffected the overall distribution of proinflammatory cytokineTNF-𝛼 in the entire periodontal complex. Breakdown andcompromise of coronal attachment shifted physiologicalfunction into an impaired function mode that in turn ledto accelerated tissue adaptation to meet functional demands,including increased secondary cementum formation. Over-all, this study adds to the understanding of periodontal

disease progression and prompts future studies to considerbiomechanical changes in addition to biochemical and mor-phological changes in periodontal disease and other cases ofjoint inflammation.

3. Development

Craniofacial development encompasses numerous pre- andpostnatal processes, including growth of the cranium by bothendochondral and intramembranous ossification, develop-ment of soft tissues including salivary glands, tongue, and themusculature, and odontogenesis, wherein two separate sets ofteeth form in humans (the primary and secondary dentition),with each tooth home to three distinct mineralized tissues,the enamel, dentin, and cementum. The morphogenesis andgrowth of dental and craniofacial tissues is influenced by neu-ral crest cells, cell-cell communications, and environmentalfactors.

Proper development of themandibular cartilage is impor-tant for growth andmineralization of themandible. However,while endochondral ossification of the axial and appendicularskeletal elements is well studied, the mandibular cartilages,which derive from ectomesenchyme of the first pharyngealarch, are often overlooked or assumed to operate under asimilar differentiation program as cartilage with differentorigins. In their paper, “An immunohistochemistry studyof Sox9, Runx2, and Osterix expression in the mandibularcartilages of newborn mouse,” H. Zhang et al. investigated thedevelopmental expression pattern of three key transcriptionfactors, Sox9, Runx2, and Osterix, in cartilages of the mousemandible. Interestingly, the authors report an overlappingexpression pattern for Sox9 and Runx2 in mandible that isdistinct from limb bud cartilage. Furthermore, despite similarlocalization of Osterix in mandibular secondary cartilagescompared to limb bud, an intense expression of this factor inthe degrading portion of Meckel’s cartilage of the mandiblesuggests a role in the ongoing processes there, possiblyeven phenotypic conversion of these chondrocytes. Overall,these data provide valuable information on an understudiedaspect of mandibular development, providing insights fordisease mechanisms in conditions such as agnathia andmicrognathia, for example.

The reorientation and fusing of the palatal shelves arecritical steps in formation of the secondary palate, wheredevelopmental defects can lead to cleft palate or cleft lipand palate. It has been hypothesized that changes in extra-cellular matrix (ECM) are involved in raising of the palatalshelves to the horizontal position and, further, that epithelial-mesenchymal interactions may be involved in the fusion ofthe palatal shelves. A. Hirata et al., in their paper, investigatedthe developmental expression of heparanase and its substrate,heparin sulfate, in the ECM during palate formation inmice. These authors documented heparanase expression inthe medial epithelial seam in palatal shelves in the processof fusing, in parallel with expression of additional ECMremodeling enzymes, matrix metalloproteinases 2, 3, and 9,where expression of heparin sulfate, perlecan, laminin, andcollagen type IV was depleted. The distribution of this panelof ECM enzymes is consistent with the hypothesis that they

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play a role in palatal ECM remodeling and proper fusion ofthe hard palate.

Salivary gland function is essential not only for eating butalso for speaking and prevention of dental decay. Reducedsalivary gland function can result from diseases such asSjogren’s Syndrome and as a result of therapeutic radiation fortreatment of head and neck cancers. Great strides have beenmade in understanding salivary gland function, and a phase1 clinical trial currently underway at the National Institute ofDental and Craniofacial Research (NIDCR) is evaluating thepotential for gene therapy using water channel Aquaporin 1(AQP1) to improve salivary flow in patients with radiation-induced damage to parotid gland function (ClinicalTrials.govNCT00372320). While salivary gland epithelial cell differen-tiation and branching have been the subject of intense study,the mesenchymal cell component is less well understood.K. Janebodin et al. employed a transgenic reporter mouseto study submandibular salivary gland mesenchyme in vivoand in vitro, developing an approach to study epithelial-mesenchymal interactions in vitro in order to better under-stand how signals such as TGF-𝛽1 affect cell differentiationand formation of the functional acinus.

Teeth also form by crosstalk between the specializedodontogenic epithelium and ectomesenchyme arising frommigrating cranial neural crest cells. The ameloblasts, highlyspecialized secretory cells derived from the epithelium, syn-thesize the enamel of the tooth crown, a unique epithelialmineralized tissue that is the hardest tissue in the humanbody. H. Li et al. studied the role of multifunctional mem-brane protein NUMB in a variety of dental cells, includingameloblasts, odontoblasts, and dental pulp cells, and foundthat interaction of this factor with the notch signaling path-waymay have regulatory effects on ameloblast differentiation“Expression and function of NUMB in odontogenesis”. Greaterunderstanding of ameloblast differentiation is critical forunderstanding hereditary enamel defects, as well as effortstowards regenerating enamel or bioengineering teeth fromdental stem cells, as the enamel organ is completely lost uponeruption of teeth, leaving no known progenitor cells behind.

Enamelin is a component of the enamel extracellularmatrix, and mutations in the associated ENAM gene causeautosomal dominant amelogenesis imperfecta, marked bythin or pitted, easily abraded enamel and, in some cases,enamel aplasia. Lower body weight in Enam null miceprompted A. H.-L. Chan et al. to study the potential forenamel defects to influence body weight, operating withthe hypothesis that dental pain arising from defective toothstructure causes reduced nutritional intake. The authorsdiscovered that the significantly decreased average litter bodyweight of Enam null mice was improved by implementing asoft chowdiet over the first sixweeks of life. Because enamelinis ameloblast specific, this effect on body weight is likelyoccurring via the interaction between the defective enamelphenotype and reduced ability to feed on a hard diet.The factthat food hardness becomes an important variable in bodyweight gain inmicewith defective dentition can provide somemechanistic insight into the relationship between compro-mised oral health and poor growth in children, where dentalcaries and dental pain and sensitivity may contribute to poornutrition.

4. Regeneration

Despite a wide range of approaches, periodontal therapiesare currently unpredictable, few are truly regenerative, andmany lack a biologic foundation. Research has shown thatperiodontal disease can be successfully treated, with biolog-ical periodontal tissue regeneration (i.e., return to structureand function of cementum, PDL, and bone) in some cases.Q. Li et al. focus on platelet-rich fibrin (PRF) as a potentialscaffold for periodontal regeneration.The PRF technique wasdeveloped from platelet-rich plasma (PRP) which has beenused to promote healing and regenerate bone and periodontaltissues. For PRP, platelets are concentrated and activated withthrombin and calcium chloride to promote instant release ofgrowth factors and cytokines. In contrast, PRF is not activatedby thrombin or anticoagulants and releases growth factorsgradually. In vitro, PRF increasedmarkers of proliferation anddifferentiation in periodontal progenitor cells, and isolateduse of the major PRF component, fibrin, replicated theseeffects. Further, in vivo studies in mice supported that PRFpromoted integration and soft tissue healing, andpilot studiesplacing PRF in peri-implant locations in two human patientswere associated with new alveolar bone formation.

Finally, in their review article, T. A. El-Bialy andAlhadlaqcreate a primer on therapeutic approaches for underdevel-oped mandibles, covering bite-jumping (functional) appli-ances, low intensity pulsed ultrasound (LIPUS), hormonetreatment, photobiomodulation, and gene therapy. Whilethese techniques hold promise for improving health out-comes for children with mandibular growth deficiency, allhave inherent limitations and challenges, as detailed by theauthors.

5. Concluding Remarks

This special issue of Biomed Research International show-cases a unique collection of 11 papers that serve as touch-stones for several areas of dental-craniofacial research forlike-minded researchers, clinicians, and students, as well asscientists in other disciplines.These papers touchmany of theexciting aspects of these fields in recent years, and we hopethey will stimulate thought and further research to betterunderstand these aspects of human health. Researchers andclinicians have never been better positioned to understandmechanisms of development, disease, and regeneration ofdental and craniofacial tissues and, in turn, to apply thatknowledge to make clinically meaningful advances.

Brian L. FosterYong-Hee P. ChunErica L. Scheller

Zhao LinChad M. NovinceAvina Paranjpe

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