Periodontitis is a chronic inflammatory disease that leads to osteoclast-mediated bone destruction, resulting in tooth loss. The cytokine TGF-beta initially promotes the inflammatory response, but ultimately slows bone loss by suppressing bone degradation. On the basis of published reports and our preliminary data, it appears likely that an important component of this repression is the initiation of osteoclast apoptosis. Reducing osteoclast numbers through targeting osteoclast survival pathways may provide important future therapeutic targets to slow pathological bone loss during periodontitis, osteoporosis, and tumor-driven osteolysis. It is the goal of this research to define the molecular pathways linking TGF- beta to regulation of osteoclast apoptosis. In preliminary studies, we observed that (i) osteoclast survival is due to continual activation of the MEK/ERK and AKT/NF(B survival pathways; (ii) PI3K coordinately activates these pathways to promote osteoclast survival; and (iii) TGF-beta induces apoptosis in surviving osteoclasts by repression of these survival pathways. These data have led to our central hypothesis that purified osteoclasts survive due to activation of survival pathways while TGF-a suppresses survival pathways to elevate osteoclast apoptosis. To test our hypothesis, the Aims of this proposal are to: (1) resolve the role of the MEK/ERK pathway in osteoclast survival. (2) establish the role of the AKT/NFkappaB pathway in osteoclast survival. (3) elucidate the cross-talk between the AKT/NFkappaB and MEK/ERK pathways in promoting osteoclast survival. (4) determine the mechanisms by which TGF-beta targets survival-promoting signaling pathways to induce osteoclast apoptosis. Understanding osteoclast apoptosis regulation may provide important avenues for therapies to slow bone degradation during pathological bone loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014680-05
Application #
7066050
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shum, Lillian
Project Start
2003-08-06
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
5
Fiscal Year
2006
Total Cost
$349,281
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Ruan, Ming; Pederson, Larry; Bradley, Elizabeth W et al. (2010) Transforming growth factor-{beta} coordinately induces suppressor of cytokine signaling 3 and leukemia inhibitory factor to suppress osteoclast apoptosis. Endocrinology 151:1713-22
Bradley, Elizabeth W; Ruan, Ming M; Oursler, Merry J (2008) PAK1 is a novel MEK-independent raf target controlling expression of the IAP survivin in M-CSF-mediated osteoclast survival. J Cell Physiol 217:752-8
Bradley, Elizabeth W; Ruan, Ming M; Vrable, Anne et al. (2008) Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem 104:1439-51
Bradley, Elizabeth W; Ruan, Ming M; Oursler, Merry J (2008) Novel pro-survival functions of the Kruppel-like transcription factor Egr2 in promotion of macrophage colony-stimulating factor-mediated osteoclast survival downstream of the MEK/ERK pathway. J Biol Chem 283:8055-64
Gingery, Anne; Bradley, Elizabeth W; Pederson, Larry et al. (2008) TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival. Exp Cell Res 314:2725-38
Khosla, Sundeep; Westendorf, Jennifer J; Oursler, Merry Jo (2008) Building bone to reverse osteoporosis and repair fractures. J Clin Invest 118:421-8
Cicek, Muzaffer; Iwaniec, Urszula T; Goblirsch, Michael J et al. (2007) 2-Methoxyestradiol suppresses osteolytic breast cancer tumor progression in vivo. Cancer Res 67:10106-11
Maran, A; Gorny, G; Oursler, M J et al. (2006) 2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts. J Cell Biochem 99:425-34
Subramaniam, Malayannan; Gorny, Genevieve; Johnsen, Steven A et al. (2005) TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of osteoclast differentiation in vitro. Mol Cell Biol 25:1191-9
Oursler, Merry Jo; Bradley, Elizabeth W; Elfering, Sarah L et al. (2005) Native, not nitrated, cytochrome c and mitochondria-derived hydrogen peroxide drive osteoclast apoptosis. Am J Physiol Cell Physiol 288:C156-68

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