Potter, Greller, Cho, Nuttall, Stroup, Suva, Tobin, 2005

Model Structure

Pulsatile administration of the parathyroid hormone (PTH) has been shown to stimulate bone formation in both animals and humans, and the PTH signalling pathway is considered as a potential target for the development of new therapeutic treatments for post-menopausal osteoporosis. The binding of PTH to its specific receptor, the PTH Type 1 receptor (PTH1R) initiates signal transduction cascades that result in bone turnover and, as such, PTH has recently been approved as a treatment for post-menopausal osteoporosis. However, while pulsatile PTH exposure results in bone formation, paradoxically, continuous PTH administration causes net bone loss.

To date, the mechanisms underlying these two phenomena remain poorly understood. To add further complexity to the conundrum, the PTH-mediated signalling pathway in osteoblasts is a complicated network that stems from the interaction of the PTH-PTH1R complex and two distinct G proteins. The identities of the various components of this signalling network remain relatively elusive,To effectively utilise PTH as a therapeutic treatment for osteoporosis it is essential to improve our understanding of the dynamics of PTH-PTH1R binding and signal transduction. To this end, Potter et al. have developed a mathematical model which simulates the PTH1R kinetics (summarised in the figure below). They use this model to explore the hypothesis that the dynamics of the receptor are critical to the bone growth or loss responses to pulsatile or continuous PTH dosing patterns respectively. Conversely, if the receptor kinetics are not crucial to the differential response, an alternative hypothesis is that downstream signal transduction events are more influential.

Simulation results suggest the model is biologically relevant and is capable of discriminating between pulsatile and continuous PTH dosing. Furthermore, the simulation results were considered to be consistent with the hypothesis that PTH1R kinetics are important in mediating the PTH effects on the skeleton.

Schematic diagram of the two-state model for PTHR1 binding kinetics PTH is secreted and/or dosed at a rate D and binds to the active (Ra) and inactive (Ri) forms of the receptor. PTH-PTHR1 binding results in the formation of the active (Ca) and inactive (Ci) complexes. In addition, there is a conversion between the active and inactive forms of the receptor and complexes, while unbound PTH is cleared from the system.

The complete original paper reference is cited below:

Response to continuous and pulsatile PTH dosing: a mathematical model for parathyroid hormone receptor kinetics, Laura K. Potter, Larry D. Greller, Carolyn R. Cho, Mark E. Nuttall, George B. Stroup, Larry J. Suva, and Frank L. Tobin, 2005, Bone , 37, 159-169. (Full text and PDF versions of the article are available to journal subscribers on the Bone website.) PubMed ID: 15921971

This model has been translated into two variant CellML models; the first CellML model considers the effects of continuous PTH administration while the second describes the consequences of pulsatile PTH dosing.

Source
Derived from workspace Potter, Greller, Cho, Nuttall, Stroup, Suva, Tobin, 2005 at changeset 5a3fc2158228.
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