Functional domains of bone sialoprotein in dentoalveolar development and healing

骨唾液蛋白在牙槽发育和愈合中的功能域

• 批准号: 10392346
• 负责人: Michael B. Chavez
• 金额: $ 4.67万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392346
• 关键词: Ablation; Adult; Affect; Age; Alveolar Bone Loss; Alzheimer' s Disease; Arginine; Aspartate; Atomic Force Microscopy; Binding; Biological; Biological Assay; Biology; Bone Diseases; Bone Regeneration; Bone remodeling; C-terminal; CRISPR/Cas technology; Caring; Cell Culture Techniques; Cell Line; Cells; Cementoblast; Collagen; Collagen Fiber; Collagen Fibril; Collagen Type I; Complex; Connective Tissue; Crystallization; Defect; Dental; Dental Cementum; Dental Implants; Deposition; Development; Diabetes Mellitus; Disease; Esthetics; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fibrillar Collagen; Fracture; Gel; Gene Expression; Genes; Genetic; Glycine; Glycoproteins; Goals; Health; Heart Diseases; Histology; Human body; Hydrophobicity; Hydroxyapatites; Implantation procedure; In Vitro; Individual; Injury; Integrin Binding; Integrins; Joints; Knock-in; Knock-out; Knowledge; Left; Ligand Binding; Link; Location; Mastication; Mechanics; Minerals; Modeling; Mus; Mutant Strains Mice; Mutation; N Domain; N-terminal; Natural regeneration; Odontogenesis; Oral health; Osteoblasts; Osteogenesis; Osteoporosis; Peptides; Periodontal Diseases; Periodontal Ligament; Phenotype; Physiologic calcification; Planet Earth; Play; Polyglutamic Acid; Population; Postmenopause; Premature Birth; Process; Proteins; Quality of life; Rattus; Role; Serum; Siblings; Signal Transduction; Skeletal Development; Skeleton; Speech; Structure; System; Testing; Therapeutic; Time; Tissues; Tooth Loss; Tooth structure; Transgenic Mice; Woman; alveolar bone; base; biomineralization; bone; bone fragility; bone healing; bone repair; bone sialoprotein; cost; craniofacial; efficacy outcomes; efficacy testing; fragility fracture; healing; human old age (65+); improved; in vivo; insight; long bone; member; microCT; mineralization; novel; novel therapeutics; outcome prediction; practical application; repaired; skeletal; substantia spongiosa; tissue regeneration; tissue repair

Abstract: Oral health is vital for overall health and quality of life, as exemplified by the importance of teeth in mastication, speech, and esthetics, and by recent connections made between oral health and diabetes, heart disease, preterm birth, and Alzheimer's disease. Periodontal disease, the breakdown of the connective tissues around the teeth, is one of the most prevalent diseases on earth, affecting 47% of adults and 70% of adults over the age of 65. The periodontal complex is a unique joint composed of two hard tissues, cementum and alveolar bone, and an intervening and unmineralized periodontal ligament (PDL). Periodontal disease leads to destruction of periodontal tissues and tooth loss if left untreated. Therapeutic approaches to regenerate or repair periodontal tissues are unpredictable at present, in part because of gaps in knowledge regarding molecules guiding dental and periodontal development. Our goal is to more successfully promote periodontal tissue repair, regeneration, and return to function. Factors directing cementum and alveolar bone mineralization are key for proper periodontal development and function, and likely play important roles in tissue repair. Bone sialoprotein (gene: Ibsp; protein: BSP) is an extracellular matrix protein highly expressed during cementum and alveolar bone formation. BSP has several putative biological roles based on its highly conserved functional domains involved in collagen binding (hydrophobic N-terminal domain), hydroxyapatite nucleation (polyglutamic acid sequences), and RGD-integrin cell signaling (C-terminal motif). BSP was demonstrated to be important in skeletal development, as genetic ablation in Ibsp knockout (Ibsp-/-) mice resulted in a skeletal phenotype marked by mildly delayed long bone mineralization and reduced trabecular bone remodeling. However, ablation of BSP causes even more dramatic effects in dentoalveolar tissues, where Ibsp-/- mice exhibited lack of cementum, severely hypomineralized alveolar bone, disrupted dental attachment, periodontal breakdown, and tooth loss. We hypothesize that BSP directs osteoblast function and mineralization activities and plays an important role in periodontal and alveolar bone repair. We will test this hypothesis in the following three aims: Aim 1: Define the binding location of BSP on type I collagen to define spatial mechanisms by which BSP may contribute to ECM mineralization. Aim 2: Elucidate the mechanistic roles of the RGD integrin-binding domain and the collagen- binding domain using newly generated cementoblast cell lines and mutant mice with a knock-in mutation inactivating the RGD motif. Aim 3: Investigate the efficacy of BSP to enhance alveolar bone healing using exogenous native rat BSP (nBSP) to investigate its use as a therapeutic in promoting alveolar bone repair. Importantly, insights gained will aid not only in regeneration of alveolar bone surrounding teeth or necessary for dental implant placement, but will also be potentially applicable towards healing critical size bone defects and fractures, and ameliorating or reversing systemic bone disorders such as osteoporosis.

文摘: