A defective bone remodeling is the physiopathologic basis of most metabolic bone diseases, including postmenopausal and age-dependent osteoporosis. Normal bone remodeling involves the synchronized activity of osteoblasts and osteoclasts within basic multicellular units and results in a cyclical succession of bone resorptive and formative phases. This orderly cellular activity requires a continuous supply of bone-forming cells and efficient mechanisms of cell-cell interactions in the bone microenvironment. Osteoblasts express several members of the cadherin family of cell adhesion molecules, which mediate calcium-dependent cell- cell adhesion. Because cell adhesion molecules constitute the master switches that drive tissue development and regeneration, it is hypothesized that the expression of cadherins by osteoblasts is critical to their maturation and function as bone-forming cells, and to the maintenance of normal cell-cell interactions in bone, and that defects in cadherin expression may be responsible for metabolic bone disease. This proposal will analyze the expression and regulation of cadherins during osteoblast differentiation, and determine the function of cadherin-mediated cell-cell adhesion for osteoblast biology. Expression and cellular localization of cadherins will be monitored during in vitro differentiation of human osteoblast precursors, and their presence in bone tissue will be verified by in situ immunohistochemistry and hybridization of histologic sections. Using immunologic techniques and transfection experiments, the role of cadherins in osteoblast cell adhesion will also be determined. Furthermore, inhibitory peptides and truncated cadherins with inhibitory activity will be used in human models of osteoblasts to analyze the role of cadherins in osteoblast biologic activity and development. If cell-cell recognition and adhesion is important for osteoblast differentiation and/or function as a bone- forming cell, deregulation of cell-cell contact and signal exchanges within the bone microenvironment may lead to decreased bone formation, thus providing a possible pathogenetic mechanism for the decreased mean wall thickness of trabecular packets that characterizes the histologic appearance of postmenopausal and aging osteoporotic bone. Therefore, the research proposed in this application, by analyzing the expression and function of cadherins in osteoblasts, is intended to help elucidate one of the basic mechanisms that regulate bone remodeling in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043470-02
Application #
2457985
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1996-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Di Benedetto, Adriana; Watkins, Marcus; Grimston, Susan et al. (2010) N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. J Cell Sci 123:2640-8
Salazar, Valerie S; Mbalaviele, Gabriel; Civitelli, Roberto (2008) The pro-osteogenic action of beta-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity. J Cell Biochem 104:942-52
Lai, Chung Fang; Cheng, Su-Li; Mbalaviele, Gabriel et al. (2006) Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice. J Bone Miner Res 21:1897-906
Mbalaviele, Gabriel; Shin, Chan Soo; Civitelli, Roberto (2006) Cell-cell adhesion and signaling through cadherins: connecting bone cells in their microenvironment. J Bone Miner Res 21:1821-7
Mbalaviele, Gabriel; Sheikh, Sharmin; Stains, Joseph P et al. (2005) Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 94:403-18
Stains, Joseph P; Civitelli, Roberto (2005) Cell-to-cell interactions in bone. Biochem Biophys Res Commun 328:721-7
Stains, Joseph P; Civitelli, Roberto (2005) Cell-cell interactions in regulating osteogenesis and osteoblast function. Birth Defects Res C Embryo Today 75:72-80
Castro, Charlles H M; Shin, Chan Soo; Stains, Joseph P et al. (2004) Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis. J Cell Sci 117:2853-64
Stains, Joseph P; Civitelli, Roberto (2003) Genomic approaches to identifying transcriptional regulators of osteoblast differentiation. Genome Biol 4:222
Jorgensen, Niklas R; Henriksen, Zanne; Sorensen, Ole H et al. (2002) Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors. J Biol Chem 277:7574-80

Showing the most recent 10 out of 15 publications