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Abstract: FR-PO511

In Silico Model of PTH-Induced Self-Limiting Anti-Apoptotic Signaling Pathways in Osteoblasts

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Cherif, Alhaji, Renal Research Institute, New York, New York, United States
  • Fuertinger, Doris H., Fresenius Medical Care, Bad Homburg, Germany
  • Thijssen, Stephan, Renal Research Institute, New York, New York, United States
  • Kotanko, Peter, Renal Research Institute, New York, New York, United States
Background

Cyclical and continuous stimulations of cell receptors result in differential responses with important clinical and therapeutic implications. An example of such differential response is seen in the anabolic and catabolic outcomes of intermittent and continuous elevations of parathyroid hormones (PTH), respectively, where chronic level of PTH, as seen in hyperparathyroidism, leads to catabolic effects on bone, whereas cyclical administration of PTH or analogs, as seen in osteoporotic therapy, stimulates osteoblastic activities resulting in anabolic gains. The goal is to develop an in silico model describing the proteasomal proteolysis mechanism limiting the anti-apoptotic effect of PTH in osteoblasts, in order to understand quantitatively the differential clinical responses.

Methods

We develop a model to describe the underlying PTH-induced intracellular osteoblastic signaling pathway, namely, Runx-2-CREB-Bcl-2 signaling pathway. The model incorporates multiple scale to capture scale differences between the anti-apoptotic and degradative enzymatic activities. The model is used to evaluate apoptotic activities under the conditions of continuously and intermittently elevated PTH, respectively.

Results

In silico result shows that continuously elevated PTH increases degradative enzymatic activities and blunt the anti-apoptotic effects associated with the Runx-2-CREB-Bcl-2 signaling pathway. The directional difference between CREB and Runx-2 equilibrates Bcl-2 level, thereby nullifying its anti-apoptotic effects on osteoblasts. Consequently, PTH-mediated osteoclastic activities via RANK-RANKL-OPG pathway exert catabolic loss. The model also predicts that intermittency of PTH increases CREB while only intermittently decreasing Runx-2, resulting in a net increase in Bcl-2. This, in conjunction with downstream inhibition of cytokine-mediated osteoblastic apoptosis, leads to anabolic gains. Employing global sensitivity analysis, different anti-apoptotic therapeutic directions are outlined.

Conclusion

There is a great need to understand the mechanisms underlying differential osteoanabolic and catabolic responses induced by intermittent and continuous levels of PTH, respectively, in order to provide new therapeutic options for patients. With our model, we can demonstrate importance of Runx-2-CREB-Bcl-2 signaling in limiting the osteoblastic apoptosis.