Osteoblasts play a central role in both normal bone remodeling and the pathogenesis of most bone diseases, including periodontal disease and abnormal craniofacial development. In addition to their role as the primary osteoid producing cell, they play an equally important role as regulatory cells. This regulatory function is a combination of the osteoblast's ability to perceive a set of specific signals (afferent) and to respond to those signals by regulating the activity of associated cells (efferent). These signals function both in paracrine and, in some cases, autocrine circuits with bone cells and are pleiotropic in regulating cells in both the hematopoietic and immune cell systems. Although differences exist between the afferent and efferent signals, most are thought to be soluble factors. However, our knowledge of them is incomplete, particularly on the efferent arm. How these factors are involved in osteoblast activation and how osteoblasts subsequently activate other cells is poorly understood. Therefore, a better understanding of the mechanisms of how osteoblasts are activated, the way osteoblasts activate associated cells, and the differentiation of osteoblasts is of central importance to our understanding of normal and altered bone remodeling. The long term goal of this work is to study the mechanisms of osteoblast activation and differentiation and concomitant cytokine release utilizing functional, serological, biochemical and molecular techniques. Three distinct but related specific aims will be examined. We will: 1) Identify and characterize the mast cell growth factor activity (MGF) novel to bone cells; 2) Determine the role osteoblast cell surface determinants plays in cell to cell activation; and 3) Determine the role the cell surface determinants Ly-6 and Thy-1 play in osteoblast differentiation and activation. Primary murine osteoblasts and the osteoblast cell line MC3T3 will be activated with osteotropic agents (LPS, PTH, IL-1, etc.) or antibodies to specific cell surface determinants. Functional, serological and biochemical experiments will be used to identify the MGF activity and other relevant cytokines. Molecular techniques (Northern blotting, mRNA stability and transcription rates) will be used to monitor changes at the molecular level. Osteoblasts will be chemically fixed and their ability to activate associated cells by cell to cell contact analyzed. Osteoblast differentiation will be followed by expression of cell surface determinants on inducible precursor cell lines. The elucidation of osteoblast development and activation, cell surface composition, and method of delivering activation signals will certainly lead to a better understanding of normal bone remodeling, fracture repair and the incorporation of both bone and tooth implants. Moreover, these experiments will add to our understanding of altered bone remodeling associated with such diseases as periodontal disease, Paget's, bone loss due to malignancy and osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR040073-04
Application #
3160377
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1989-06-20
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, X D; Qian, H Y; Neff, L et al. (1999) Thy-1 antigen expression by cells in the osteoblast lineage. J Bone Miner Res 14:362-75
Horowitz, M C; Friedlaender, G E; Qian, H Y (1996) The immune response: the efferent arm. Clin Orthop Relat Res :25-34
Greenfield, E M; Horowitz, M C; Lavish, S A (1996) Stimulation by parathyroid hormone of interleukin-6 and leukemia inhibitory factor expression in osteoblasts is an immediate-early gene response induced by cAMP signal transduction. J Biol Chem 271:10984-9
Levy, J B; Schindler, C; Raz, R et al. (1996) Activation of the JAK-STAT signal transduction pathway by oncostatin-M cultured human and mouse osteoblastic cells. Endocrinology 137:1159-65
Horowitz, M C; Fields, A; DeMeo, D et al. (1994) Expression and regulation of Ly-6 differentiation antigens by murine osteoblasts. Endocrinology 135:1032-43
Greenfield, E M; Gornik, S A; Horowitz, M C et al. (1993) Regulation of cytokine expression in osteoblasts by parathyroid hormone: rapid stimulation of interleukin-6 and leukemia inhibitory factor mRNA. J Bone Miner Res 8:1163-71