Primary hyperparathyroidism (PHP) is a common cause of accelerated bone loss and osteoporosis. In spite of extensive investigation the mechanism of the bone catabolic action of PTH has not been not been completely elucidated. PHP is also an important cause of increased bone turnover, which is an independent risk factor for fractures. Studies in 4 in vivo and 5 in vitro models suggest that T cells provide survival, proliferative and pro-osteoclastogenic signals to bone marrow (BM) stromal cells (SCs) through the membrane-bound costimulatory molecule CD40L. As a result, T cell deficient mice are protected against PTH induced bone loss. This is due to the fact that BM SCs derived from T cell deficient mice are fewer in number, produce lower amounts of osteoclastogenic cytokines, and lack the capacity to support PTH induced osteoclast (OC) formation. The capacity of T cells to upregulate both the number and the osteoclastogenic activity of SCs is abolished by silencing of the PTH receptor PPR in T cells. We thus hypothesize that PTH directly stimulates T cells to promote SC osteoclastogenic activity by signaling through the PTH receptor PPR, and that T cells regulate SC number and activity through CD40L. The goal of this application is to determine the mechanism by which T cells mediate the bone catabolic activity of PTH.
In Specific Aim 1 we will determine the phenotype of the T lymphocytes which are regulated by PTH, and mediate PTH induced bone loss. This will be accomplished by evaluating the effect of continuous PTH treatment in mice lacking specific T cell subsets.
In Aim 2 we will determine the role of direct PPR signaling in T cells in PTH induced OC formation and bone loss. This will be accomplished by utilizing T cells from conditional KO mice which lack the PTH receptor in T cells. We will also determine if PPR signaling in T cells stimulate OC formation by generating T cell signals which upregulate the osteoclastogenic activity of SCs, and if PPR signaling in T cells increases their production of RANKL, TNF and IL-1, and their expression of CD40L.
In Aim 3 we will determine if the capacity to regulate SC osteoclastogenic activity in a spontaneous fashion (as opposed to in response to PTH stimulation) and if in vivo silencing of CD40L prevent the increase in SC osteoclastogenic activity, OC formation and bone loss induced by PTH. The discovery of new mechanisms of action of PTH is relevant to public health as it may lead to the identification of novel therapeutic targets for PHP, osteoporosis and the bone disease associated with end stage renal disease. Our studies may also provide insights on strategies for augmenting the anabolic activity of intermittent PTH treatment. One such strategy could be that of antagonizing T cell production of osteoclastogenic factors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR054625-01A1
Application #
7314433
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2007-08-24
Project End
2012-06-30
Budget Start
2007-08-24
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$328,950
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Neale Weitzmann, M; Pacifici, Roberto (2017) Parathyroid Diseases and T Cells. Curr Osteoporos Rep 15:135-141
Li, Jau-Yi; Chassaing, Benoit; Tyagi, Abdul Malik et al. (2016) Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 126:2049-63
Pacifici, Roberto (2016) The Role of IL-17 and TH17 Cells in the Bone Catabolic Activity of PTH. Front Immunol 7:57
Alvarez, Jessica A; Ziegler, Thomas R; Millson, Erin C et al. (2016) Body composition and lung function in cystic fibrosis and their association with adiposity and normal-weight obesity. Nutrition 32:447-52
Pacifici, Roberto (2016) T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci 1364:11-24
Straub, Rainer H; Cutolo, Maurizio; Pacifici, Roberto (2015) Evolutionary medicine and bone loss in chronic inflammatory diseases--A theory of inflammation-related osteopenia. Semin Arthritis Rheum 45:220-8
Robinson, Jerid W; Li, Jau-Yi; Walker, Lindsey D et al. (2015) T cell-expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment. J Bone Miner Res 30:695-705
Li, Jau-Yi; D'Amelio, Patrizia; Robinson, Jerid et al. (2015) IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice. Cell Metab 22:799-810
Li, Jau-Yi; Walker, Lindsey D; Tyagi, Abdul Malik et al. (2014) The sclerostin-independent bone anabolic activity of intermittent PTH treatment is mediated by T-cell-produced Wnt10b. J Bone Miner Res 29:43-54
Pacifici, Roberto (2013) Role of T cells in the modulation of PTH action: physiological and clinical significance. Endocrine 44:576-82

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