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is: Friday, October 10 08:32 PM |
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Roberto Pacifici, M.D.Division Director
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Division of Endocrinology, Emory University
1639 Pierce Drive, WMRB
Atlanta, GA 30322
Phone (404) 727-1391; Fax (404) 727-1300Education and Employment
1981 MD |
M.D.-Undergraduate/graduate combined program Perugia University School of Medicine, Perugia, Italy, Summa Cum Laude |
1981-1984 |
School of Specialization in Internal Medicine, Perugia University School of Medicine, Perugia, Italy, Summa Cum Laude |
1984-1988 |
Fellowship in Endocrinology and
Metabolism, Div.of Bone & Mineral Metabolism, |
1988-1993 |
Assistant Professor of Medicine, 7/1/88 - 6/30/93 Washington University School of Medicine |
1995-2000 |
Assistant Professor of Radiology, Mallinkrodt Institute of Radiology |
1993-2000 |
Associate Professor of Medicine, Washington University School of Medicine |
2000-2003 |
Sydney M. and Stella H. Shoenberg Professor of Medicine Division of Bone and Mineral Metabolism, Washington University School of Medicine |
2000-2003 |
Professor of Radiology, Mallinkrodt Institute of Radiology |
2003- |
Division Director; Endocrinology
and Metabolism |
Honors
National Osteoporosis Foundation Research Award 1988
Fuller Albright Young Investigator Award, American Society of Bone and Mineral Research 1995Research Program
The main focus of our laboratory is on the mechanism of action of estrogen in bone. We were the first to report that monocytic production of IL-1, TNF and GM-CSF (cytokines recognized for their ability to stimulate bone resorption) increases after natural or surgical menopause and is blocked by estrogen replacement. We also demonstrated the treatment of ovariectomized animals with the IL-1 inhibitor IL-1ra and the TNF inhibitor TNFbp prevents bone loss in ovariectomized animals. The increased production of IL-1 and TNF caused by estrogen deficiency induces bone loss by inducing the differentiation of bone marrow stromal cells into a phenotype characterized by increased M-CSF production and increased pro-osteoclastogenic activity. More recently we have defined the molecular mechanism of this phenomenon and demonstrated that estrogen decreases the phosphorylation of the transcription factors Egr-1, leading to increased association of Egr-1 with Sp-1, and decreased nuclear levels of free Sp-1. This leads, in turn to decreased M-CSF mRNA transcription.
Studies are also in progress to determine the molecular mechanism by which estrogen down-regulates TNF gene expression in monocytes. We have uncovered that estrogen blocks the production of JunD and its phosphorylation, leading to decreased AP-1 induced TNF transcription. Recently we have also developed a new method for generating human osteoclasts from peripheral blood cells of healthy donors. Using this technique we have demonstrated that stromal cells are not an absolute requirements for human osteoclastogenesis. We are currently using differential display technique to identify estrogen regulated genes in human osteoclasts.
Our studies are supported by NIH grants from NIAMS and NIDDK as well as several grants from industry.
Training Experience
Dr. Pacifici was Director of the Training Program in Bone and Mineral Metabolism at Washington University.
Recent Publications
S. Srivastava., N.M. Weitzmann, S. Cenci. S. Adler and R. Pacifici 1999 Estrogen decreases AP-1 induced TNF gene expression by blocking JNK activity. J. Clin. Invest. 104: 503-510
S. Cenci, N.M. Weitzmann, and R. Pacifici 2000 M-CSF neutralization and Egr-1 deficiency prevent ovariectomy induced bone loss. Evidence for a key role of M-CSF in the bone-sparing effect of estrogen. J. Clin. Invest. 105: 1279-1287.
N.M. Weitzmann, S. Cenci. J. Haug, C. Brown, J. DiPersio and R. Pacifici 2000 B-Lymphocytes Inhibit Human Osteoclastogenesis by Secretion of TGFb J. Cell. Biochem. 78: 318-324
M. N. Weitzmann, S. Cenci, L. Rifas, C. Brown, and R. Pacifici 2000 IL-7 Stimulates Osteoclast Formation by Upregulating the T-cell Production of Soluble Osteoclastogenic Cytokines. Blood. 96:1873-1878.
S. Cenci, M.N. Weitzmann, C. Roggia, N. Namba, D. Novack, and R. Pacifici. 2000 Estrogen deficiency induces bone loss by enhancing T cell production of TNFa. J. Clin. Invest. 106: 1229-1237.
M.N. Weitzmann, S. Cenci, L. Rifas, J. Haug, J. DiPersio and R. Pacifici. 2001 T-cell Activation Induces Human Osteoclast Formation via RANKL Dependent and Independent Mechanisms. J. Bone Miner. Res. 16: 328-337.
S. Srivastava., N.M. Weitzmann, S. Cenci, F.P. Ross and R. Pacifici, 2001. Estrogen decreases osteoclast formation by down regulating RANK expression and RANKL induced JNK activation. J. Biol. Chem. 276:8836-8840.
C. Roggia, Y. Gao, M.N. Weitzmann, G. Toraldo, S. Cenci,J. Kindle G. Isaia, and R. Pacifici. 2002. Upregulation of TNF producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Natl. Acad.Sci. USA 98:13960-13965.
M. N. Weitzmann, C. Roggia, L. Weitzmann, G. Toraldo and R. Pacifici. 2002 Increased Production of IL-7 Uncouples Bone Formation from Bone Resorption During Estrogen Deficiency. J. Clin. Invest. 110:1643-1650.