Browsing by Subject "Bone"
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Item Bivalent Ligand MMG22 Reduces Bone Cancer Pain without Tolerance or Sedation(2022-07) Shueb, SarahPain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by the application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw.Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesic, whose ED50 was orders of magnitude lower than morphine. Moreover, the ED50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or altered motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR5, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.Item Bone Morphogenetic Protein-2 (BMP2) upregulates osteoclast gene expression.(2009-11) Espe, Kelly ChristineBone Morphogenetic Proteins (BMPs) induce bone formation by osteoblasts, but their direct role in bone resorption by osteoclasts remains to be characterized. Twisted Gastrulation (Twsg1) is a secreted BMP binding protein that inhibits BMPs from binding to their receptors. Mice lacking the Twsg1 gene (Twsg1-/-) exhibit an osteopenic skeletal defect. Previous studies indicate that the osteopenic phenotype in Twsg1-/- mice is due to increased osteoclastogenesis and not due to reduced osteoblast function. This study hypothesizes that treatment of wild-type osteoclasts with BMP2 will increase osteoclast gene expression and that this gene expression will decrease with the addition of the known BMP inhibitor, Noggin. The results of this investigation show that the addition of BMP2 to RANKL upregulates Cathepsin K, Nfatc1, Acp5, DCSTAMP, and ATP6v6d02 gene expression levels. The addition of the more well understood BMP inhibitor, Noggin, downregulates these gene expression levels. These results indicate a possible direct mechanism of action for BMP2 on osteoclast activation.Item Cone Beam Computed Tomography Evaluation of Buccal Alveolar Bone Changes Following Rapid Maxillary Expansion and Fixed Appliance therapy(2020-06) Sperl, AdamIntroduction: Rapid maxillary expansion (RME) and fixed appliance therapy are commonly used to treat maxillary transverse deficiencies, but the treatment causes buccal displacement of appliance anchor teeth, which can damage the periodontium. Clinical decision making may be improved by better understanding how this treatment affects the periodontium. Objectives: The purpose of this study was to assess factors that might affect buccal bone changes adjacent to the permanent maxillary first molar after RME and fixed appliance therapy. Methods: Pre-treatment (T1) and post-treatment (T2) cone-beam computed tomography (CBCT) scans were obtained from 45 patients treated with RME and fixed appliance therapy. Measurements of buccal alveolar bone thickness adjacent to the mesiobuccal root of the maxillary first molar were made on CBCT images at 4 mm (B4), 6 mm (B6), and 8 mm (B8) from the CEJ. Anatomic defects of the buccal bone were recorded. T-tests were performed to compare T1 and T2 alveolar bone thickness and to determine whether teeth with post-treatment anatomic defects had thinner initial bone. Correlation analyses were conducted to examine the relationship between buccal alveolar bone thickness changes and the following variables: prescribed expansion, age at T1, time between T1 and T2, post-expansion retention time, and initial bone thickness. Results: There was a statistically significant reduction in buccal alveolar bone thickness from T1 to T2. 47.7% of teeth and 60% of patients had anatomic defects after treatment. Teeth with T2 anatomic defects had significantly thinner buccal bone at T1. Reduction in alveolar bone was correlated with only one tested variable: initial bone thickness. Conclusions: RME and fixed appliance therapy can result in a significant reduction in buccal alveolar bone thickness and an increase in anatomic defects adjacent to the expander anchor teeth. Anchor teeth with greater initial buccal bone thickness are likely to have a greater reduction in buccal bone thickness. Anchor teeth with thin initial buccal bone are more likely to develop post- treatment anatomic defects of the buccal bone plate.Item The effect of radial convection on cell proliferation Iin bone tissue engineering(2009-04) Shao, WeiruLarge bone defects are frequently encountered during surgeries. Traditional methods of repair are limited by bone graft availability and increased surgical morbidity. Tissue engineered bone tissue has many clinical advantages. However, its current technology is limited by implant size and lacks of immediate nutritional perfusion once the tissue is implanted. Objective: To sustain cell growth and proliferation in a three-dimensional scaffold unit with radial convective flow. Material and Methods: Fetal rat calvarial cells were harvested and loaded into 1x1 cm hydroxyapatite cylinders. Microperforated hollow fibers were placed at the center of the cylinders to generate radial convective flow with oxygenated cell culture medium under hydraulic pressure. Live cell densities within the blocks were determined after 8 days of convection. Results: Radial convection sustained cell growth and proliferation better than simple diffusion at all three zones of the cylinders: center, outer, and rim. Conclusion: Radial convective flow is capable of supporting cellular function and proliferation in small scaffold units. The design of the radial convection units and their system parameters are validated by this study. The results are very useful to devise future tissue engineering studies involving radial convective flow.Item A lymphoid enhancer binding factor (Lef) 1 isoform regulates osteoblast maturation.(2010-03) Hoeppner, Luke HilbertThe canonical Wnt signaling pathway has emerged as an important regulator of bone formation, regeneration and repair. Studies over the past decade have demonstrated that activation of canonical Wnt signaling generally promotes osteoblast proliferation and enhances bone mass, while suppression of Wnt signaling results in bone loss. Gaining a better understanding of Wnt signaling in the context of skeletal metabolism is important because current skeletal regeneration and repair treatments have limitations, anti-resorptive therapies have unknown long-term health consequences and the demand for therapies is rising as our population ages. Osteoporosis is a growing healthcare challenge that affects about 44 million Americans. Cancer survival rates drop drastically in patients suffering from bone metastases. A complete, molecular understanding of the canonical Wnt signaling cascade in the context of skeletal biology will promote the development of new therapies for the treatment of osteoporosis, skeletal cancer metastasis, and other skeletal diseases that result in uncoupling of bone formation and resorption. Lymphoid Enhancer Binding Factor (Lef) 1 is a transcription factor in the canonical Wnt/The canonical Wnt signaling pathway has emerged as an important regulator of bone formation, regeneration and repair. Studies over the past decade have demonstrated that activation of canonical Wnt signaling generally promotes osteoblast proliferation and enhances bone mass, while suppression of Wnt signaling results in bone loss. Gaining a better understanding of Wnt signaling in the context of skeletal metabolism is important because current skeletal regeneration and repair treatments have limitations, anti-resorptive therapies have unknown long-term health consequences and the demand for therapies is rising as our population ages. Osteoporosis is a growing healthcare challenge that affects about 44 million Americans. Cancer survival rates drop drastically in patients suffering from bone metastases. A complete, molecular understanding of the canonical Wnt signaling cascade in the context of skeletal biology will promote the development of new therapies for the treatment of osteoporosis, skeletal cancer metastasis, and other skeletal diseases that result in uncoupling of bone formation and resorption. Lymphoid Enhancer Binding Factor (Lef) 1 is a transcription factor in the canonical Wnt/Lrp5/6/β-catenin signaling cascade, which regulates osteoblast differentiation, bone density and skeletal strength. In this thesis, I describe the expression and function of an alternative Lef1 isoform in osseous cells. Lef1ΔN is a naturally occurring isoform driven by a promoter (p2) within the intron between exons 3 and 4 of Lef1. Lef1ΔN is induced during late osteoblast differentiation. This is opposite to the expression pattern of the full-length Lef1 protein, which as we previously showed, decreases during differentiation. We showed that the Lef1ΔN p2 promoter is active in osteoblasts and Runx2 positively regulates its activity. BMP2 also promotes Lef1ΔN expression, whereas Wnt3a represses it. Lef1ΔN overexpression in differentiating osteoblasts induced osteocalcin and type 1 collagen expression, which suggests Lef1ΔN is a crucial regulator of terminal differentiation in osseous cells. We found Lef1ΔN interacts with β-catenin to activate a Lef1-responsive promoter and stimulate the transcription of genes involved in late osteoblast differentiation. We mapped the region of Lef1ΔN that associates with β-catenin to an element within the first 61 amino acids of Lef1ΔN and showed this region was required to induce type 1 collagen and osteocalcin expression during osteoblast maturation. Taken together, Lef1ΔN interacts with β-catenin to regulate terminal differentiation in osseous cells.Item Mechanisms underlying the regulation and functions of HDAC7 in osteoclast differentiation(2013-06) Cho, JangYeun JaniceThe purpose of this research is to characterize the regulation and functions of Histone Deacetylase 7 (HDAC7) in osteoclast differentiation. Histone Deacetylases (HDACs) are negative regulators of transcription.1 Endochondral bone formation including maturation of chondrocytes and osteoblasts is regulated by HDACs.2 It has been shown that the suppression of HDAC7 enhanced osteoclast formation while the overexpression of myc-HDAC7 inhibits osteoclast formation.3 Hence, it has been suggested that the stimulation of HDAC7 might be a unique therapeutic strategy to reduce osteoclastic bone loss.3 However, the mechanism and the molecular pathways regulating how HDAC7 inhibits osteoclast formations have not been examined. In this study, we hypothesized that the deacetylase catalytic activity of HDAC7 is necessary for suppression of osteoclast formation. It is also hypothesized that the subcellular localization of HDAC7 in nucleus facilitated by the phosphorylation of serine residues at N- terminal with Receptor activator of nuclear factor-kappaB ligand (RANKL) stimulation is the one of the mechanism that HDAC7 controls osteoclast differentiation. However, from this study, it is found that HDAC7 deacetylase activity is dispensable for HDAC7-mediated inhibition of osteoclastogenesis. It is also concluded that the presence of HDAC7, not necessarily the localization of HDAC7 in the nucleus, is necessary to repress the osteoclastogenesis.Item Revisiting Harold Frost’s mechanostat theory of bone functional adaptation: new interpretations based on new evidence.(2011-01) Hughes, Julie MarieThe main purpose of this dissertation is to explore, update, and add to the existing theory of bone functional adaptation through critically reviewing and interpreting the literature in the bone field. In this dissertation, three main questions are asked regarding bone functional adaptation and then answered (based on existing literature) in three papers. These questions are: 1. What is the underlying biology of how bones sense and respond to mechanical stimuli? 2. Does bone functional adaptation become less effective with increasing age? 3. Do the benefits of bone functional adaptation transfer to protection from osteoporotic fractures? The final chapter summarizes the main conclusions of the dissertation and outlines important implications for both future bone research and for prevention of osteoporosis and related fractures.Item Uncovering Mechanisms of Osteosarcoma Metastasis(2016-08) Marko, TracyOsteosarcoma (OS) is the most common primary malignant bone tumor, with metastatic disease responsible for most treatment failure and patient death. A better understanding of the metastatic disease state is needed to improve patient survival. The studies presented here explore a variety of questions surrounding metastatic OS. A literature search of the PubMed database was conducted to compare the prevalence of metastatic OS at diagnosis across countries. The average prevalence of metastasis at diagnosis increased as Human Development Index score (HDI) decreased, with an 18% global average. In countries with medium/low HDI, where more barriers to accessing healthcare exist, the higher prevalence of metastasis may result from treatment delay or an artificially inflated prevalence due to patients with less severe symptoms not presenting to clinic. Canine OS is a naturally occurring, spontaneous disease with more rapid disease progression and greater incidence than human OS. An understanding and utilization of studies on metastatic OS in dogs could help identify new treatment strategies to improve patient outcomes in humans and dogs. We evaluated the similarities of metastatic OS between the species by comparing risk factors for having metastatic OS at diagnosis between pet dogs from our veterinary clinic and pediatric patients in the Surveillance, Epidemiology, and End Results database. Here we build on current knowledge of canine OS by showing that primary tumors in similar anatomical locations metastasize at comparable rates in both species. A Sleeping Beauty mutagenesis screen previously conducted in our laboratory identified Slit-Robo GTPase- Activating Protein 2 (SRGAP2) as a potential suppressor of OS metastasis. SRGAP2 controls phenotypes in neurons supporting the hypothesis that it may suppress migration in the context of cancer. Although the effects of SRGAP2 in OS were not consistent across all cell lines, they tended to support this hypothesis. Additionally, expression levels of other genes in the Slit-Robo pathway were significantly altered in a subset of mouse and human OS, and SRGAP2 protein expression was lost in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in OS metastasis, with loss of SRGAP2 contributing to a more aggressive phenotype.