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.
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