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Metropolitan Government of Nashville-Davidson (balance), TN, United States

Sterling J.A.,Tennessee Valley Healthcare System VISN | Sterling J.A.,Vanderbilt University | Guelcher S.A.,Vanderbilt University
Current Osteoporosis Reports | Year: 2014

Healing fractures resulting from osteoporosis or cancer remains a significant clinical challenge. In these populations, healing is often impaired not only due to age and disease, but also by other therapeutic interventions such as radiation, steroids, and chemotherapy. Despite substantial improvements in the treatment of osteoporosis over the last few decades, osteoporotic fractures are still a major clinical challenge in the elderly population due to impaired healing. Similar fractures with impaired healing are also prevalent in cancer patients, especially those with tumor growing in bone. Treatment options for cancer patients are further complicated by the fact that bone anabolic therapies are contraindicated in patients with tumors. Therefore, many patients undergo surgery to repair the fracture, and bone grafts are often used to stabilize orthopedic implants and provide a scaffold for ingrowth of new bone. Both synthetic and naturally occurring biomaterials have been investigated as bone grafts for repair of osteoporotic fractures, including calcium phosphate bone cements, resorbable polymers, and allograft or autograft bone. In order to re-establish normal bone repair, bone grafts have been augmented with anabolic agents, such as mesenchymal stem cells or recombinant human bone morphogenetic protein-2. These developing approaches to bone grafting are anticipated to improve the clinical management of osteoporotic and cancer-induced fractures. © 2014 Springer Science+Business Media. Source

Sterling J.A.,Tennessee Valley Healthcare System VISN | Sterling J.A.,Vanderbilt University | Johnson R.W.,Tennessee Valley Healthcare System VISN | Johnson R.W.,Vanderbilt University
International Journal of Cancer Research and Prevention | Year: 2012

Breast cancer frequently metastasizes to distant organs such as lung and bone where tumors cause changes in the local micro-environment. These alterations often lead to bone destruction or bone formation and can cause pain, hypercalcemia, and increased fracture rates in patients. Several small animal models have been developed that are capable of producing pathogenesis strikingly similar to the clinical condition in both tumor burden and bone disease. In order to fully investigate these animal models, many imaging techniques have been applied with most focusing on either imaging the tumor or changes in bone. Radiography using Faxitron analysis has been the central tool for researchers for 20 years, but other techniques have developed that allow for more comprehensive analysis. Over the past 10 years, imaging tumors in bone has primarily been performed using tumor cells over-expressing fluorescent proteins or luciferase. Both approaches have been very successful due to rapid data output, no radiation, and cost-effectiveness, but are both limited in resolution and in the ability to detect small tumors that are deep in the bone. Therefore, new technologies are emerging that utilize the near-infrared (NIR) spectra, which has a longer wavelength and allows for imaging tumors deeper within the body and has lower background than fluorescent imaging. Not only can NIR proteins be transfected like fluorescent proteins, but antibodies can also be conjugated with NIR to detect the expression of specific proteins in vivo. Other emerging techniques for imaging tumors in bone are positron emission tomography (PET) imaging and magnetic resonance imaging (MRI), both of which are commonly used clinically for diagnosing tumors in bone, but are not applied frequently for animal studies due to high cost and limited throughput. However, both approaches can give valuable information in animal studies. For imaging tumor-induced effects on bone, Faxitron analysis still remains the primary method of analysis, but in recent years micro-Computed Tomography (μCT) analyses have gained popularity due to the ability to obtain high resolution 3-dimensional images. While the highest resolution images can be obtained by ex vivo scanners, such as the Scanco μCT, the utility of these scanners is obviously limited to endpoint analyses. This limitation has recently stimulated the advancement of in vivo μCT analyses in breast cancer-induced osteolysis which can be performed longitudinally without affecting tumor cell growth due to high-dose radiation. Live animal μCT can also be combined with other imaging techniques such as MRI, μPET, and μSPECT (single photon emission computed tomography). Additionally, both μSPECT and μPET technologies have been applied to bone to image bone turnover and allow investigators to analyze changes in bone that have been caused by the presence of tumor. Finally, investigators are currently developing technologies to fuse multiple imaging modalities together to give a comprehensive understanding of tumor-induced bone disease. While there remains significant room for improvement, current imaging modalities can, in combination, provide an accurate and dynamic reflection of breast tumor burden and bone destruction in small animal models and have helped propagate significant advances in our understanding of tumor metastasis to bone. © Nova Science Publishers, Inc. Source

Johnson R.W.,Tennessee Valley Healthcare System VISN | Johnson R.W.,Vanderbilt University | Merkel A.R.,Tennessee Valley Healthcare System VISN | Merkel A.R.,Vanderbilt University | And 5 more authors.
Clinical and Experimental Metastasis | Year: 2014

Parathyroid hormone-related protein (PTHrP) is an important regulator of bone destruction in bone metastatic tumors. Transforming growth factor-beta (TGF-β) stimulates PTHrP production in part through the transcription factor Gli2, which is regulated independent of the Hedgehog signaling pathway in osteolytic cancer cells. However, inhibition of TGF-β in vivo does not fully inhibit tumor growth in bone or tumor-induced bone destruction, suggesting other pathways are involved. While Wnt signaling regulates Gli2 in development, the role of Wnt signaling in bone metastasis is unknown. Therefore, we investigated whether Wnt signaling regulates Gli2 expression in tumor cells that induce bone destruction. We report here that Wnt activation by β-catenin/T cell factor 4 (TCF4) over-expression or lithium chloride (LiCl) treatment increased Gli2 and PTHrP expression in osteolytic cancer cells. This was mediated through the TCF and Smad binding sites within the Gli2 promoter as determined by promoter mutation studies, suggesting cross-talk between TGF-β and Wnt signaling. Culture of tumor cells on substrates with bone-like rigidity increased Gli2 and PTHrP production, enhanced autocrine Wnt activity and led to an increase in the TCF/Wnt signaling reporter (TOPFlash), enriched β-catenin nuclear accumulation, and elevated Wnt-related genes by PCR-array. Stromal cells serve as an additional paracrine source of Wnt ligands and enhanced Gli2 and PTHrP mRNA levels in MDA-MB-231 and RWGT2 cells in vitro and promoted tumor-induced bone destruction in vivo in a β-catenin/Wnt3a-dependent mechanism. These data indicate that a combination of matrix rigidity and stromal-secreted factors stimulate Gli2 and PTHrP through Wnt signaling in osteolytic breast cancer cells, and there is significant cross-talk between the Wnt and TGF-β signaling pathways. This suggests that the Wnt signaling pathway may be a potential therapeutic target for inhibiting tumor cell response to the bone microenvironment and at the very least should be considered in clinical regimens targeting TGF-β signaling. © 2014, US Government. Source

Johnson R.W.,Tennessee Valley Healthcare System VISN | Johnson R.W.,Vanderbilt University | Merkel A.R.,Tennessee Valley Healthcare System VISN | Merkel A.R.,Vanderbilt University | And 6 more authors.
Anticancer Research | Year: 2011

Background: Breast cancer cells frequently metastasize to bone, where they up-regulate their expression of the transcription factor GLI2 and the downstream osteolytic factor parathyroid hormone-related protein (PTHrP). The guanosine nucleotide 6-thioguanine (6-TG) inhibits PTHrP expression and blocks osteolytic bone destruction in mice inoculated with bone metastatic cells; however, the mechanism by which 6-TG inhibits PTHrP remains unclear. We hypothesized that 6-TG inhibition of PTHrP is mediated through GL12 signaling. Materials and Methods: Human MDA-MB-231 breast cancer cells and RWGT2 squamous-cell lung carcinoma cells were treated with 100 μM 6-TG and examined for GL12 mRNA expression and stability by Q-PCR, promoter activity by luciferase assay, and protein expression by Western blot. Results: 6-TG significantly blocked GLI2 mRNA and protein expression, but did not affect stability. Additionally, 6-TG directly inhibited GLI2 promoter activity, and when cells were transfected with constitutively expressed GL12, the inhibitory effect of 6-TG on PTHrP expression was abolished. Conclusion: Taken together, these data indicate that 6-TG regulates PTHrP in part through GLI2 transcription, and therefore the clinical use of 6-TG or other guanosine nucleotides may be a viable therapeutic option in tumor types expressing elevated levels of GLI proteins. Source

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