Our program is focused on the interrelationships of cell structure and gene expression that mediate osteoblast proliferation and differentiation during progressive development of the bone cell phenotype. Our working hypothesis is that nuclear structure (the nuclear matrix, chromatin structure, matrix-chromatin interactions, and higher order chromatin functional domains) contributes to the onset, progression and maintenance of osteoblast phenotypic properties by participating in the regulation of gene expression both at the transcriptional level and at a series of post-transcriptional levels. Equally important, we are postulating that nuclear structure is regulated by the expression of genes related to phenotypic properties of the bone cell. We will pursue an integrated team approach to experimentally address molecular mechanisms whereby nuclear structure regulates developmental expression of cell growth and bone cell-related genes in normal diploid osteoblasts. Mechanisms by which cell structure facilitates the integration of physiological regulatory signals (1,25(OH)2D3, dexamethasone and TGFBeta) that support osteoblast growth and differentiation will be explored. Parallel studies will be carried out with osteosarcoma cells where stringent growth control is abrogated, an organized extracellular matrix is not developed and genes associated with expression of the mature osteoblast phenotype, which in normal diploid osteoblasts are expressed post-proliferatively, are actively expressed in proliferating osteosarcoma cells. The relationship of cell structure to the expression of genes required for osteoblast proliferation and differentiation will provide valuable insight into the cellular molecular basis of both normal skeletal development and metabolic bone disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
1P01AR042262-01A1
Application #
2081436
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1994-05-01
Project End
1998-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Shopland, L S; Byron, M; Stein, J L et al. (2001) Replication-dependent histone gene expression is related to Cajal body (CB) association but does not require sustained CB contact. Mol Biol Cell 12:565-76
Lian, J B; Stein, G S; Stein, J L et al. (1999) Regulated expression of the bone-specific osteocalcin gene by vitamins and hormones. Vitam Horm 55:443-509
Stein, G S; van Wijnen, A J; Stein, J L et al. (1999) Implications for interrelationships between nuclear architecture and control of gene expression under microgravity conditions. FASEB J 13 Suppl:S157-66
Lynch, M P; Capparelli, C; Stein, J L et al. (1998) Apoptosis during bone-like tissue development in vitro. J Cell Biochem 68:31-49
Zeng, C; McNeil, S; Pockwinse, S et al. (1998) Intranuclear targeting of AML/CBFalpha regulatory factors to nuclear matrix-associated transcriptional domains. Proc Natl Acad Sci U S A 95:1585-9
Shalhoub, V; Aslam, F; Breen, E et al. (1998) Multiple levels of steroid hormone-dependent control of osteocalcin during osteoblast differentiation: glucocorticoid regulation of basal and vitamin D stimulated gene expression. J Cell Biochem 69:154-68
Lindenmuth, D; van Wijnen, A J; Penman, S et al. (1998) TGF-beta1 modifications in nuclear matrix proteins of osteoblasts during differentiation. J Cell Biochem 69:291-303
Bagchi, M; Ansari, S A; Lindenmuth, D M et al. (1998) Nuclear matrix associated DNA-binding proteins of ocular lens epithelial cells. Mol Biol Rep 25:13-9
Stein, G S; van Wijnen, A J; Stein, J L et al. (1998) Linkages of nuclear architecture to biological and pathological control of gene expression. J Cell Biochem Suppl 30-31:220-31
Stein, G S; van Wijnen, A J; Stein, J L et al. (1998) Interrelationships of nuclear structure and transcriptional control: functional consequences of being in the right place at the right time. J Cell Biochem 70:200-12

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