Mechanical forces provide a crucial sensory input to the skeleton, but the precise mechanisms by which this input is translated into anabolic and remodeling responses is unclear. Here, we propose pilot studies designed to implicate PTHrP as a mediator of the effects of force on bone. The PTHrP gene is known to be stretch-induced; PTHrP is a normal osteoblastic product, and PTHrP has been shown to regulate L-type voltage-sensitive calcium channel (L-VSCC) Ca2+ influx, regarded as a critical component of the osteoblastic anabolic response.
In Aim 1, we propose that mechanotransduction will increase PTHrP secretion by osteoblasts and osteoblast-like cells. Here, we envision the following sequence: 1) stretch-induced opening of the stretch-activated- cation channel leading to depolarization of the cell, 2) depolarization- induced opening of a specific L-VSCC (alpha1c-containing) and 3) Ca2+- induced PTHrP secretion.
In Aim 2, we will examine the effects of PTHrP (1-34) on osteoblastic cells. Of several anticipated responses, the most important will be the opening of a second L-VSCC (alpha1d-containing), generating a sustained Ca2+ influx. This sustained Ca2+ response is expected to further increase regulated PTHrP secretion as well as transcription of the PTHrP gene and is presumed to be the key signal that will translate directly into an anabolic osteoblastic response.
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