This is an application for an Independent Scientist Award (ISA) K02. The applicant is a very productive, experienced, and NIH- funded investigator. Her research focuses on cytokine signal transduction in osteoblastic cells and its effects on bone remodeling. The applicant works in a rich and productive environment provided by the Center for Osteoporosis and Metabolic Bone Diseases at the University of Arkansas for Med. Sciences. Her work as an independent investigator demonstrated that osteoblastic cells display receptors for IL-6 type cytokines (IL- 6, IL-11, LIF, CNTF, and OSM); that receptor activation induces differentiation and prevents apoptosis of osteoblastic cells; and that, in an osteoblastic cell line, cytokine effects require the transcriptional activation of the cyclin dependent kinase inhibitor p21WAF1, SDI1, CIP1. In addition, cells representing different stages of differentiation express different receptor repertoire, and receptor expression is modulated by systemic hormones. Based on this, she proposes the following interrelated working hypotheses: IL-6 type cytokines promote differentiation and prevent apoptosis of osteoblastic cells by regulating the expression of p21WAF1, SDI1, CIP1. Different receptor repertoires are expressed at different stages of osteoblast differentiation in vivo, and systemic hormones influence the differentiating and anti-apoptotic effects of the cytokines by modulating receptor expression. To test these hypotheses, she proposes to: 1) Investigate the mechanism of the anti-apoptotic effect of the cytokines using MG-63 osteoblastic cells and p21 deficient osteoblasts, and transfections with dominant negative and constitutively or inducibly active molecules of the cytokine signaling pathway. 2) Determine the effects of systemic hormones on receptor expression; and examine whether these changes alter cell responses to the cytokines. And, 3) Determine the pattern of distribution of cytokine receptors in osteoblastic cells in vivo, in murine bone marrow cell aspirates and sections of undecalcified bone from mice, by in situ RT-PCR in combination with histostaining and dynamic bone histomorphometry. The K02 award will permit the applicant to focus her research on cytokine signaling in bone and to enhance her cell/molecular biology skills, as the immediate goals; and to achieve scientific maturity in a uniquely strong environment as her academic career progresses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02AR002127-01A1
Application #
6129908
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Sharrock, William J
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2000-09-15
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$72,082
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Bellido, Teresita (2014) Osteocyte-driven bone remodeling. Calcif Tissue Int 94:25-34
Plotkin, Lilian I; Bellido, Teresita (2013) Beyond gap junctions: Connexin43 and bone cell signaling. Bone 52:157-66
Bivi, Nicoletta; Condon, Keith W; Allen, Matthew R et al. (2012) Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 27:374-89
Bivi, Nicoletta; Lezcano, Virginia; Romanello, Milena et al. (2011) Connexin43 interacts with ?arrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone. J Cell Biochem 112:2920-30
Bellido, Teresita; Plotkin, Lilian I (2011) Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 49:50-5
Plotkin, L I; Bivi, Nicoletta; Bellido, T (2011) A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice. Bone 49:122-7
Plotkin, Lilian I; Lezcano, Virginia; Thostenson, Jeff et al. (2008) Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res 23:1712-21
Plotkin, Lillian I; Manolagas, Stavros C; Bellido, Teresita (2007) Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem 282:24120-30
Aguirre, J Ignacio; Plotkin, Lilian I; Gortazar, Arancha R et al. (2007) A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction. J Biol Chem 282:25501-8
Aguirre, J Ignacio; Plotkin, Lilian I; Stewart, Scott A et al. (2006) Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res 21:605-15

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