Project Summary In the United States, 47% of adults 30 years or older are affected by periodontal disease, and this rate increases with age to 70% in adults 65 years or older. The periodontal complex, consisting of alveolar bone, cementum, gingiva, and the periodontal ligament (PDL), works to ensure proper tooth attachment and nourishment, distribute occlusal forces, maintain alveolar bone height, and protect the periodontium from invading microbes. Periodontal disease leads to the destruction of one or more of these tissues, which ultimately results in partial or total edentulism as well as reduced function of the masticatory complex, self- esteem, and interpersonal relationships. Most therapies are unpredictable as well as unsuccessful at repairing all three lost or damaged tissues. Bone sialoprotein (Ibsp gene; BSP protein) is a multifunctional, extracellular matrix protein found in mineralized tissues of the skeleton and dentition, including alveolar bone and cementum. Total knockout mice (Ibsp-/-) display reduced acellular cementum, hypomineralized alveolar bone, PDL detachment, severe alveolar bone resorption, tooth loss, and periodontal destruction. To date, nearly all studies on BSP focus on its roles in cranial and postcranial development. However, its dual functions in osteoblasts and osteoclasts also suggest an important role in the coupled process of bone remodeling; Ibsp-/- mice show dramatic defects in alveolar bone socket healing following molar extraction. While the importance of BSP in the periodontal complex is evident, its molecular functions remain unclear. We propose BSP is a key molecule in periodontal development, homeostasis, and repair. The outlined experiments will test our central hypothesis that BSP modulates periodontal development and repair through its functions in key cells for periodontal function: cementoblasts, osteoblasts, and osteoclasts. The overall objectives of this proposal are: 1.) define the origin of BSP and cementoblast lineage using conditional ablation of Ibsp from ectomesenchymal vs. epithelial cell populations; 2.) elucidate the role(s) of BSP in osteoblast and osteoclast function(s) in alveolar bone healing by conditionally ablating Ibsp from osteoblasts and osteoclasts; and 3.) determine the role of BSP in postmenopausal osteoporotic changes to bone metabolism using an ovariectomy (OVX) rodent model of postmenopausal osteoporosis. The knowledge gained from this proposal holds promise for the development of novel and reparative therapies of the periodontal complex. Successful completion of the proposed research will provide key insights into the function(s) of BSP in periodontal biology as well as diseases characterized by excessive osteoblast-osteoclast decoupling.

Project Narrative Periodontal disease is one of the most common diseases afflicting the oral cavity and leads to periodontal destruction as well as tooth loss; while current treatments aim to mitigate symptoms and prevent further disease progression, they do not truly repair the already lost or damaged periodontal tissues. Bone sialoprotein (BSP) is an extracellular matrix protein found in mineralized tissues of the skeleton and dentition, including tissues of the periodontal complex (i.e., cementum and alveolar bone). The proposed studies will elucidate how BSP modulates periodontal development and repair through its functions in key cells for periodontal function: cementoblasts, osteoblasts, and osteoclasts, which will ultimately facilitate the development of reparative therapies for periodontal tissues.