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Browsing by Author "Helms, Jill A."
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Item Aberrantly elevated Wnt signaling is responsible for cementum overgrowth and dental ankylosis(Elsevier, 2018) Wu, Yan; Yuan, Xue; Perez, Kristy C.; Hyman, Sydnee; Wang, Liao; Pellegrini, Gretel; Salmon, Benjamin; Bellido, Teresita; Helms, Jill A.; Anatomy and Cell Biology, School of MedicineVertebrate teeth are attached to the jawbones using a variety of methods but in mammals, a fibrous connection is the norm. This fibrous periodontal ligament (PDL) allows teeth to move in the jawbones in response to natural eruptive forces, mastication, and orthodontic tooth movement. In some disease states the PDL either calcifies or is replaced by a mineralized tissue and the result is ankylosis, where the tooth is fused to the alveolar bone. To understand how the PDL maintains this fibrous state we examined a strain of mice in which tooth movement is arrested. DaβcatOt mice express a stabilized form of β-catenin in DMP1-positive alveolar bone osteocytes and cementocytes, which results in elevated Wnt signaling throughout the periodontium. As a consequence, there is an accrual of massive amounts of cellular cementum and alveolar bone, the PDL itself calcifies and teeth become ankylosed. These data suggest that to maintain its fibrous nature, Wnt signaling must normally be repressed in the PDL space.Item A Correlation between Wnt/Beta-catenin Signaling and the Rate of Dentin Secretion(Elsevier, 2019-11) Zhao, Yuan; Yuan, Xue; Bellido, Teresita; Helms, Jill A.; Anatomy and Cell Biology, School of MedicineIntroduction Odontoblasts produce dentin throughout life and in response to trauma. The purpose of this study was to identify the roles of endogenous Wnt signaling in regulating the rate of dentin accumulation. Methods Histology, immunohistochemistry, vital dye labeling, and histomorphometric assays were used to quantify the rate of dentin accumulation as a function of age. Two strains of Wnt reporter mice were used to identify and follow the distribution and number of Wnt-responsive odontoblasts as a function of age. To show a causal relationship between dentin secretion and Wnt signaling, dentin accumulation was monitored in a strain of mice in which Wnt signaling was aberrantly elevated. Results Dentin deposition occurs throughout life, but the rate of accumulation slows with age. This decline in dentin secretion correlates with a decrease in endogenous Wnt signaling. In a genetically modified strain of mice, instead of tubular dentin, aberrantly elevated Wnt signaling resulted in accumulation of reparative dentin or osteodentin secreted from predontoblasts. Conclusions Wnt signaling regulates dentin secretion by odontoblasts, and the formation of reparative or osteodentin is the direct consequence of elevated Wnt signaling. These preclinical data have therapeutic implications for the development of a biologically based pulp capping medicant.Item A novel hypothesis based on clinical, radiological, and histological data to explain the dentinogenesis imperfecta type II phenotype(Taylor & Francis, 2019) Turkkahraman, Hakan; Galindo, Fernando; Tulu, Ustun Serdar; Helms, Jill A.; Orthodontics and Oral Facial Genetics, School of DentistryPurpose/Aim: The aim of this study was to explore whether dentinogenesis imperfecta (DGI)-related aberrations are detectable in odontogenic tissues. Materials and Methods: Morphological and histological analyses were carried out on 3 teeth (two maxillary 1st molars, one maxillary central incisor) extracted from a patient with DGI Type II. A maxillary 2nd molar teeth extracted from a healthy patient was used as control. A micro-computed tomographic (μCT) data-acquisition system was used to scan and reconstruct samples. Pentachrome and picrosirius red histologic stains were used to analyze odontogenic tissues and their collagenous matrices. Results: Our findings corroborate DGI effects on molar and incisor root elongation, and the hypo-mineralized state of DGI dentin. In addition to these findings, we discovered changes to the DGI pulp cavity: Reactionary dentin formation, which we theorize is exacerbated by the early loss of enamel, nearly obliterated an acellular but still-vascularized DGI pulp cavity. We also discovered an accumulation of lamellated cellular cementum at the root apices, which we hypothesize compensates for the severe and rapid attrition of the DGI tooth. Conclusions: Based on imaging and histological data, we propose a novel hypothesis to explain the complex dental phenotypes observed in patients with DGI Type II.Item Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity(American Association for Cancer Research, 2021) Sabol, Hayley M.; Ferrari, Adam J.; Adhikari, Manish; Amorim, Tânia; McAndrews, Kevin; Anderson, Judith; Vigolo, Michele; Lehal, Rajwinder; Cregor, Meloney; Khan, Sharmin; Cuevas, Pedro L.; Helms, Jill A.; Kurihara, Noriyoshi; Srinivasan, Venkat; Ebetino, Frank H.; Boeckman, Robert K., Jr.; Roodman, G. David; Bellido, Teresita; Delgado-Calle, Jesus; Medicine, School of MedicineSystemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. SIGNIFICANCE: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.