M. Neale Weitzmann Ph.D. Assistant Professor of Medicine nweitzmann@usa.net

Division of Endocrinology, Emory University
1639 Pierce Drive, 1305 WMRB
Atlanta, GA 30322
Phone (404) 727-1391 /Fax (404) 727-1300

Education and Employment

Research Interests

Among the clinical manifestations of estrogen deficiency (postmenopausal osteoporosis), and inflammatory autoimmune diseases such as rheumatoid arthritis is pronounced bone loss. The mechanisms driving bone destruction in these debilitating maladies are poorly understood, but are known to involve the upregulation of T cell derived osteoclastogenic cytokines including Receptor Activator of NFkB Ligand (RANKL) and Tumor Necrosis Factor Alpha (TNF). The mechanisms driving the activation of T cells leading to RANKL and TNF production remain to be defined. IL-7 is a powerful lymphopoietic cytokine long known to be elevated in rheumatoid arthritis and recently shown by us to also be up-regulated during estrogen deficiency. Over the last several years we have studied the mechanisms of Interleukin-7 (IL-7) mediated bone destruction, using in vitro and in vivo models of inflammation and estrogen deficiency. Attesting to the importance of T cells in the bone wasting effect of IL-7 in vivo, we have found that while normal wild type mice undergo significant osteoclastic bone loss following IL-7 injection, nude mice, a strain deficient in T cells, are protected from IL-7 induced bone loss. Transplantation of T cells back into nude mice restores the ability of IL-7 to induce bone destruction. In addition, we have found that in vivo neutralization of IL-7 prevents bone loss in mice following surgically induced estrogen deficiency (ovariectomy). IL-7 blockade not only prevents ovariectomy induced osteoclastic bone destruction but also enhances new bone formation, suggesting that during estrogen deficiency, enhanced levels of IL-7 stimulate bone resorption while simultaneously repressing the compensatory increase in bone formation necessary to reestablish bone homeostasis. By disrupting the coupling between bone formation and bone resorption elevated levels of IL-7 ultimately lead to net bone loss. Our current research is now focused on investigating the signal transduction pathways by which IL-7 induces RANKL and TNF in T cells, and how IL-7 represses bone formation via suppression of key osteoblastic genes such as Runx2.

Laboratory Personnel

Yan Li, MD

Recent Publications

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L. Rifas, S. Arackal and M. N. Weitzmann. Inflammatory T Cells Rapidly Induce Differentiation Of Human Bone Marrow Stromal Cells Into Mature Osteoblasts. J. Cell. Biochem, 2002, In Press.

G. Toraldo, C. Roggia, W-P. Qian, R. Pacifici & M. N. Weitzmann. T cells are crucial mediators of IL-7 induced Bone Loss In Vivo. Proc. Natl. Acad. Sci (USA), 2002, In Press.

M. N. Weitzmann, C. Roggia, G. Toraldo, L. Weitzmann & R. Pacifici. Increased Production of IL-7 Uncouples Bone Formation from Bone Resorption During Estrogen Deficiency J. Clin. Invest., 2002, 110:1643-1650.

M. N. Weitzmann, S. Cenci, L. Rifas, J. Haug, J. DiPersio & R. Pacifici. T-cell Activation Induces Human Osteoclast Formation via RANKL Dependent and Independent Mechanisms. J. Bone Miner. Res, 2001, 16:328-337

M. N. Weitzmann, S. Cenci, L. Rifas, C. Brown, & R. Pacifici. IL-7 Stimulates Osteoclast Formation by Upregulating the T-cell Production of Soluble Osteoclastogenic Cytokines. Blood, 2000, 96:1873-1878.

M. N. Weitzmann, K.J. Woodford & K. Usdin, The mouse Ms6-hm hypervariable microsatellite forms a hairpin and two unusual tetraplexes. J. Biol. Chem. 1998, 273, 30742-30749

M. N. Weitzmann, K.J. Woodford & K. Usdin, DNA Secondary Structures and the Evolution of Hypervariable Tandem Arrays. J. Biol. Chem. 1997, 272, 9517-9523

M. N. Weitzmann, K.J. Woodford & K. Usdin, The Development and Use of a DNA Polymerase Arrest Assay for the Evaluation of Parameters Affecting Intrastrand Tetraplex Formation. J. Biol. Chem. 1996, 271, 20958-20964