Mechanical stress is the dominant factor in activation of bone remodeling, but the mechanism of its action on osteoblasts is largely unknown. The long term goal of the studies describe this proposal is to determine molecular mechanisms involved in transduction of mechanical stress in bone to a biological response in osteoblasts. An in vivo model of transgenic mice will be utilized to analyze transcriptional regulation of the alpha1,(l) collagen (COL1A1) gene in bone cells under mechanical stress. As the first phase of these studies, this grant focuses on characterization of the model and comparison of changes in histomorphometric parameters of bone formation with the endogenous COL1A1 gene activity. The periodontium of transgenic mice, harboring the COL1A1 promoter directing the expression of a reporter gene (CAT), will be mechanically stressed by applying a defined and reproducible force on the mandibular first molar. The response of osteoblasts covering the periodontal alveolar bone surface will be assessed by histomorphometric measurements and determining the mRNAs for endogenous collagen at tissue and cellular levels. Our first specific goal is to define the magnitude of force for optimal biological response of bone in our model. We will next identify the type of tooth movement produced by this force to determine the alveolar bone surfaces that will respond to applied force with bone formation. The second goal of the study is to determine the time courses of increase in histomorphometric measurements of bone formation and the enhanced expression of the COL1A1 gene in periodontal osteoblasts under mechanical stress. Quantitative measurements of the COL1A1 mRNA at the level of tissue and in individual periodontal cells will be used as an indicator of the endogenous collagen gene activity. The results of this study are an important prerequisite for initiation of mapping of DNA regulatory regions and identification of nuclear transcription factors which mediate genetic response of bone cells to mechanical stress.
| Pavlin, D; Gluhak-Heinrich, J (2001) Effect of mechanical loading on periodontal cells. Crit Rev Oral Biol Med 12:414-24 |
| Pavlin, D; Zadro, R; Gluhak-Heinrich, J (2001) Temporal pattern of stimulation of osteoblast-associated genes during mechanically-induced osteogenesis in vivo: early responses of osteocalcin and type I collagen. Connect Tissue Res 42:135-48 |
| Pavlin, D; Dove, S B; Zadro, R et al. (2000) Mechanical loading stimulates differentiation of periodontal osteoblasts in a mouse osteoinduction model: effect on type I collagen and alkaline phosphatase genes. Calcif Tissue Int 67:163-72 |
