The bone microenvironment of prostate carcinoma is a unique scenario where there is an accumulation of woven-like bone. This is likely associated with increases in both osteoclast and osteoblast activity that result in a net increase in immature bone. Parathyroid hormone-related protein (PTHrP) is a major mediator of bone remodeling through its anabolic and catabolic actions. Evidence from our laboratory indicates that metastatic prostate carcinoma in bone produces PTHrP, and that PTHrP has a protective effect on apoptosis in prostate epithelial cells and a pro- or anti-apoptotic in osteoblastic cells dependent on their differentiation state. These, and data from other laboratories, lead to the overall hypothesis that PTHrP derived from prostate carcinoma is responsible for dysregulated bone remodeling in the metastatic lesion as a result of increased osteoclastic and osteoblastic activity. An important mechanism for this altered bone is via the ability of PTHrP to regulate osteoblast apoptosis through the cAMP/PKA and AP-1 pathway. PTH and PTHrP signal through the cAMP/PKA pathway and activate AP-1 family members, well known for their effects in bone; however, alternate pathways exist and the specific mechanisms and pathways involved in aberrant bone remodeling present during prostate carcinoma are unknown. The studies proposed here are designed to confirm that PTHrP plays a key role in the alterations of bone remodeling present in the metastatic lesion and elucidate the mechanisms for PTHrP effects in regards to its ability to regulate osteoblast apoptosis through the cAMP/PKA and AP-1 pathway.
Three specific aims will address these mechanisms. The first will confirm that prostate carcinoma derived PTHrP is associated with increased bone resorption and formation in an animal model of prostate carcinoma in the bone microenvironment.
The second aim will determine whether the effects of PTHrP on bone formation in the metastatic lesion are associated with alterations in osteoblast apoptosis. Studies in the third aim will identify the downstream mediators of prostate carcinoma-derived PTHrP that alter apoptosis in osteoblasts. By identifying the mediators and signaling molecules of PTHrP in the metastatic lesion, these studies will provide critical information that will clarify the dependence of PTHrP for the osseous response to prostate carcinoma. This valuable information will facilitate the design of therapeutic and preventive strategies to address the debilitating condition of prostate carcinoma metastasis. Furthermore, these studies will enhance our basic knowledge as to the role of the PTH/PTHrP (PTH-1) receptor in metastatic disease.
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