Foster Lab

We study the molecular biology of tooth root development and mineralization, with interests including genes, mechanisms, diseases, and novel regeneration strategies.

Lab Projects

BSP Project microscopy

Bone Sialoprotein

Identification of bone sialoprotein (BSP) as a critical factor in cementogenesis and craniofacial bone formation. Despite being widely used as an extracellular matrix marker of cementum, the functional importance of BSP in cementum remained unknown for decades.  In the first studies of dentoalveolar tissues in Ibsp-/- mice, we identified lack of acellular cementum, recognizing the critical role for BSP in cementogenesis (Foster et al., 2013). Strikingly, due to lack of acellular cementum, the periodontal ligament (PDL) detached and became disorganized, a long junctional epithelium developed, and alveolar bone underwent destruction, leading to tooth loss (Foster et al., 2015). We have focused our attention on the several evolutionarily conserved functional domains. Inactivating the RGD integrin-binding domain of BSP in a gene-edited mouse model (IbspKAE/KAE) revealed a non-essential role for this motif in cementum and alveolar bone mineralization, though PDL structure, composition, and mechanical properties were altered (Nagasaki et al., 2022). By developing a molar extraction model, we showed that Ibsp-/- mice have a severe defect in alveolar bone healing characterized by defective quantity and quality of bone repair and dysregulated osteoblast gene expression (Chavez et al., 2022). Ongoing studies of mouse and cell models will determine the functional importance of conserved domains and test the capability of BSP to promote periodontal tissue repair.

Hypophosphatasia (HPP)

Analyzing the dentoalveolar pathology and therapies for hypophosphatasia (HPP). HPP is an inborn error-of-metabolism resulting from mutations in the gene ALPL that encodes tissue nonspecific alkaline phosphatase (TNAP), an enzyme that reduces local concentrations of the mineralization inhibitor, inorganic pyrophosphate (PPi).  HPP features defective mineralization of the skeleton and dentition.  In collaboration with Dr. Jose Luis Millán, we defined novel aspects of HPP-associated dental disease including absence/hypoplasia of acellular cementum in several mouse models of HPP, including the Alpl knock-out (Alpl-/-), the Alpl+/A116T knock-in mutation mouse, and two conditional Alpl knock-out mouse models.  We identified the mineralization defect in dentin of Alpl-/- mice to be inhibition of mineral propagation following matrix vesicle rupture in the mantle dentin, and have since analyzed mantle dentin defects in a novel sheep model of HPP (Mohamed et al., 2022) and in human patients with HPP, suggesting an important common mineralization mechanism for this region of dentin across species (Kramer et al., 2021). Conditional ablation of Alpl allows for flexible spatial or temporal targeting of gene knock-out, making possible additional HPP models for disease and therapy studies (Foster et al., 2017). In groundbreaking work in collaboration with Dr. Millán, we recently showed that a gene therapy approach consisting of a single intramuscular injection of recombinant, mineral–targeted TNAP-D10 could successfully ameliorate the majority of skeletal and dental defects arising from HPP (Kinoshita et al., 2021).  Ongoing studies including analysis to understand genotype-phenotype effects of HPP on dental tissues, development of additional mouse models of HPP with dentoalveolar effects, and assessment of therapeutic interventions.

HPP Project microscopy
XLH30

X-linked hypophosphatemia (XLH)

Analysis of dentoalveolar defects from X-linked hypophosphatemia (XLH) and treatment effects. XLH is the most common form of inherited rickets. Yet skeletal and dentoalveolar pathologies are incompletely understood, effective treatments for XLH are not established, and no treatments are available to specifically improve associated dentoalveolar defects. Use of high-resolution, quantitative micro-CT and histomorphometry allowed us to extend understanding of the phenotype beyond defects of enamel, dentin, and alveolar bone to identify osteocyte and cementocyte perilacunar defects and altered marker expression associated with hypomineralization, also for the first time using dynamic mechanical analysis (DMA) to show substantially defective periodontal mechanical properties in Hyp mice (Zhang et al., 2020). We also applied a challenge model of unopposed eruption, discovering that Hyp mouse molars did not exhibit super-eruption defects despite hypomineralized cellular cementum and severe perilacunar defects around cementocytes (Lira dos Santos, 2021). Cementocytes in both Hyp and wild-type mice showed ultrastructural alterations under super-eruption, and expression of GJA1, suggesting potential cell activity associated with mechanical response. In parallel studies, we quantitatively analyzed primary teeth from a cohort of pediatric patients with XLH, finding defects across all dentin regions, and substantial accumulation of interglobular dentin, recognizable even in mildly affected patients (Clayton et al., 2021). Most recently, we compared effects of vitamin D and FGF23-neutralizing antibody treatments on dentoalveolar development in Hyp mice, finding only limited improvement compared to biochemical and skeletal outcomes (Lira dos Santos, 2021b). Ongoing studies include identifying mechanisms for dentoalveolar pathology in XLH that are not be addressed by current therapies.

Pyrophosphate (PPi)

Defining pyrophosphate (PPi) as a critical regulator of cementum: Cementum defects from periodontal diseases or genetic disorders cause periodontal dysfunction and tooth loss.  We demonstrated that cementum formation is tuned by regulators of PPi, including tissue nonspecific alkaline phosphatase (TNAP), the progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) (Foster et al., 2012).  This paradigm-shifting work allowed for a new understanding of cementum biology, showing that cementum is distinct from bone, and that acellular and cellular cementum are under the control of different regulators.  Importantly, we demonstrated through study of dental development in human subjects with ENPP1 loss-of-function mutations, that cementum regulation via PPi extends across species, so is likely highly evolutionarily conserved (Thumbigere-Math et al., 2018).  Extending this developmental work, we demonstrated that pharmacologic manipulation of PPi through an ENPP1-Fc fusion protein could regulate cementum growth, supporting therapeutic interventions targeting PPi metabolism (Chu et al., 2020). Delivery of TNAP promoted cementum and periodontal regeneration in mouse models with genetic or surgically created periodontal defects (Nagasaki et al., 2021). Ongoing work included explorations of therapeutic efficacy of TNAP and other PPi modulators for periodontal regeneration.

Pyrophosphate microscopy
Inflammatory Periodontal

Inflammatory periodontal conditions

Dissecting novel genes and regulatory pathways in inflammatory periodontal conditions: Periodontal diseases are among the most prevalent on earth, causing periodontal tissue destruction and tooth loss, and significantly affecting oral and overall health and quality of life.  While some risk factors and indicators for periodontitis are established, many aspects are not well understood, particularly host immunity and underlying pathological mechanisms.  This is compounded by the fact that current periodontal therapies are unpredictable, few are truly regenerative, and many lack a biologic foundation.  We identified a family with hereditary multiple idiopathic cervical root resorption (MICRR) and collated more than 30 years of clinical data on the affected members (Neely et al., 2016).  Genetic testing of the affected kindred revealed a variant in interferon regulatory factor 8 (IRF8), a transcription factor that regulates differentiation of myeloid cells, including immune cells and osteoclasts (Thumbigere-Math et al., 2019).  The variant was in a highly conserved C-terminal motif, and in vivo studies revealed increased osteoclast numbers in periodontia of Irf8-/- vs. control mice, and in vitro studies revealed that genetic aberration of IRF8 enhanced many osteoclast-selective markers.  DDR1 is a collagen receptor tyrosine kinase that regulates proliferation, adhesion, migration, and differentiation in cell context-dependent manner.  In studies of dentoalveolar tissues of Ddr1-/- mice, we found normal dentoalveolar development and periodontal function, however, by 9 months of age mice exhibited bacterial invasion of periodontia, inflammation, connective tissue destruction, and tooth mobility and loss (Chavez et al., 2019).  We thus identify DDR1 as a novel and nonredundant factor regulation periodontal health.  Based on high DDR1 expression in basal epithelium and in immune cells, we hypothesize periodontal functions include epithelial barrier function and/or immune surveillance of periodontal tissues. Ongoing studies focus on identifying functions of DDR1 in periodontal biology.

Defining functions of cementocytes in cementum biology

Cellular cementum includes cementocytes, cells that resemble bone osteocytes, but whose potential functions remain undefined. In collaboration with Dr. Lynda Bonewald, an expert on osteocyte biology, we established the first immortalized line of murine cementocytes, confirming in vitro vs. in vivo expression of key markers, tracking extracellular matrix synthesis and mineralization in culture, and documenting some responses to fluid flow shear stress compared to osteocytes (Zhao et al., 2015).  Based on these insights and accumulated observations in the cementum literature, we propose that cementocytes may recapitulate some functions of osteocytes in regulating cellular cementum formation and resorption (Zhao et al. 2016). Ongoing work focused on mouse models testing cementocyte functions through gene editing or targeted cell ablation.

Cementocyte microscopy

Our Team

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Laboratory manager/ Research Assistant II

Tamara Kolli

Elis Lira dos Santos
Postdoctoral Scholar

Elis Lira dos Santos

Michael Chavez
DDS-PhD student

Michael Chavez

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DDS-PhD student

Natalie Andras

April Phanrungsuwan
PhD student

April Phanrungsuwan

Leena Eltilib
Undergraduate fellow

Leena Eltilib

Bella Donnelly
Undergraduate Fellow

Bella Donnelly

Macey Siegel
Dental Student Researcher

Macey Siegel

Daria Buhtoiarova
Dental Student Researcher

Daria Buhtoiarova

Arya Shah
Undergraduate Volunteer

Arya Shah

Dr. Foster with lab team members outside Postle Hall
Dr. Foster with lab team members outside Postle Hall

Lab Alumni

Fatma Mohamed
Prosthodontics Resident - University of Michigan School of Dentistry

Fatma Mohamed

Christina Zachariadou
Assistant Professor - University of Buffalo Dental School

Christina Zachariadou

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