OF THE OVERALL PROGRAM (taken from the application):Physical connections between extracellular matrix (ECM), cytoskeleton, and nuclear matrix may allow osteoblasts to sense mechanical perturbations and translate them into gene expression. Work is proposed to study the pathway in vivo and in vitro in cells at different maturational levels using laminar fluid forces. Project 1 will define the dynamics of osteoblast proliferation after a mechanical stimulus in vivo, and will test the effect of loading frequency on bone cell proliferation. Using two different animal models, they will determine which genes, are influenced indirectly through mechanically-induced prostaglandin and nitric oxide synthesis. The possibility that bone cells accommodate to mechanical loading will be tested using the rat ulnar loading model. Project 2 will determine the interaction of mechanosensitive ion channels (MSCC, VSCC) and intracellular calcium release (iCaR) on fluid shear-induced changes in gene expression in proliferating and differentiated osteoblasts. Regulation of channel function and iCaR by specific integrin binding to different ECM proteins and in response to fluid shear will be measured. Control of channel activation and iCaR by g-proteins in response to fluid shear will be examined using a combination of g-protein activators and inhibitors in conjunction with patch clamp anc Ca2+ imaging techniques. Project 3 will determine the role of actin filament-integrin linkages and integrin-ECM interactions in fluid shear-induced mechanotransduction. It will also determine the role of myosin light chain phosphorylation and the GTP-binding protein rho in fluid shear-induced mechanotransduction. Project 4 will determine the interaction between the poly(dT) sites of the COL1A1 promoter and nuclear matrix architectural transcription factors (NP/NMP4) in mediating the transcriptional response of COL1A1 to fluid shear. It will determine the significance of actin-ECM interactions on NP and NMP4-mediated COL1A1 response to fluid shear. These Projects are supported by three Cores: Administrative and Biostatistics; Cell Biology; Mechanical Loading. Data generated by this Program are intended to define some mechanisms by which fluid forces can regulate gene expression, and will attempt to validate these mechanisms by in vivo studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR045218-04
Application #
6628122
Study Section
Special Emphasis Panel (ZAR1-JRL-A (O2))
Program Officer
Sharrock, William J
Project Start
2000-02-23
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$910,941
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Li, Jiliang; Liu, Dawei; Ke, Hua Zhu et al. (2005) The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J Biol Chem 280:42952-9
Alam, Imranul; Robling, Alexander G; Weissing, Sarah et al. (2005) Bone mass and strength: phenotypic and genetic relationship to alcohol preference in P/NP and HAD/LAD rats. Alcohol Clin Exp Res 29:1769-76
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Schriefer, Jennifer L; Warden, Stuart J; Saxon, Leanne K et al. (2005) Cellular accommodation and the response of bone to mechanical loading. J Biomech 38:1838-45
Warden, Stuart J; Robling, Alexander G; Sanders, Megan S et al. (2005) Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146:685-93
Alvarez, Marta; Shah, Rita; Rhodes, Simon J et al. (2005) Two promoters control the mouse Nmp4/CIZ transcription factor gene. Gene 347:43-54
Norvell, S M; Alvarez, M; Bidwell, J P et al. (2004) Fluid shear stress induces beta-catenin signaling in osteoblasts. Calcif Tissue Int 75:396-404
Warden, S J; Turner, C H (2004) Mechanotransduction in the cortical bone is most efficient at loading frequencies of 5-10 Hz. Bone 34:261-70
Norvell, Suzanne M; Ponik, Suzanne M; Bowen, Deidre K et al. (2004) Fluid shear stress induction of COX-2 protein and prostaglandin release in cultured MC3T3-E1 osteoblasts does not require intact microfilaments or microtubules. J Appl Physiol 96:957-66

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