Role of Agrin and Wnt signaling inhibitor Sfrp4 on osteogenesis and odontogenesis

• Grant number: 22/02461-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2022
• End date: August 31, 2023
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Márcio Mateus Beloti
• Grantee: Maria Paula Oliveira Gomes
• Supervisor: Francesca Gori
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 21/03204-2 - Participation of agrin on osteoblast differentiation and bone tissue regeneration induced by mesenchymal stem cells in defects created in mouse calvaria, BP.DD

Abstract

Pyle's disease is a rare skeletal disorder of long bone with wide metaphysis, increased trabecular bone, cortical thinning, and increased fragility fracture risk caused by a genetic deficiency in Secreted Frizzled Receptor Protein 4 (Sfrp4). In Sfrp4 null mice, cortical thinning is due to a deregulation of periosteal bone formation and endosteal remodeling mainly because activation of non-canonical Wnt signaling. Sfrp4 functions as a Wnt signaling inhibitor, interfering Wnt ligands to interact with their receptor complexes and blocking both canonical and non-canonical Wnt cascades. The extracellular matrix protein Agrin, which is involved in several biological processes, has an important contribution to osteoblast differentiation, by modulating the Wnt signaling pathway, supporting a possible involvement of Agrin and Sfrp4 expressions in Wnt signaling-mediated osteogenesis. In addition, Pyle's disease patients present often dental manifestations including carious and misplaced teeth, taurodontism, retained deciduous teeth, delayed eruption of permanent teeth, mandibular prognathism and dental Class III-malocclusion. Considering tooth development is regulated by interactions between dental epithelium and mesenchyme through a complex signaling network, several studies have demonstrated that alterations in Wnt signaling lead to various dental anomalies such as dysmorphic, missing, and supernumerary teeth. The dental manifestations seen in Pyle's disease support a potential involvement of Sfrp4 in tooth development and mineralization and susceptibility to dental caries. The hypothesis of this study is that Agrin and Sfrp4 are involved in Wnt signaling-mediated osteoblast differentiation, and Sfrp4, via its interference with Wnt signaling, regulates epithelial-mesenchymal cells interactions and is required for proper tooth. Therefore, the aims of this study are to: 1) Investigate Agrin expression in bone marrow-derived mesenchymal stromal cells and dental pulp cells of wild-type (wt) and Sfrp4-/- mice during osteoblast and odontoblast differentiation, respectively and 2) Explore the effect of Sfrp4 deletion in dental pulp cells and tooth development. The proposed research is significant and conceptually innovative because it will advance our understanding of simultaneous activation effect of canonical and non-canonical Wnt signaling, and association of Sfrp4 and Agrin expressions (Sfrp4-/- mice) on osteogenesis and odontogenesis, and to propose alternative therapies for Pyle's disease patients. (AU)