Browsing by Subject "Osteolysis"

Now showing 1 - 5 of 5
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    Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells
    (Impact Journals, 2016-11-29) Taipaleenmäki, Hanna; Farina, Nicholas H.; van Wijnen, Andre J.; Stein, Janet L.; Hesse, Eric; Stein, Gary S.; Lian, Jane B.; Department of Anatomy & Cell Biology, IU School of Medicine
    Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo. These findings indicate a positive role for miR-218-5p in bone metastasis. Bioinformatic and biochemical analyses revealed a positive correlation between aberrant miR-218-5p expression and activation of Wnt signaling in breast cancer cells. Mechanistically, miR-218-5p targets the Wnt inhibitors Sclerostin (SOST) and sFRP-2, which highly enhances Wnt signaling. In contrast, delivery of antimiR-218-5p decreased Wnt activity and the expression of metastasis-related genes, including bone sialoprotein (BSP/IBSP), osteopontin (OPN/SPP1) and CXCR-4, implicating a Wnt/miR-218-5p regulatory network in bone metastatic breast cancer. Furthermore, miR-218-5p also mediates the Wnt-dependent up-regulation of PTHrP, a key cytokine promoting cancer-induced osteolysis. Antagonizing miR-218-5p reduced the expression of PTHrP and Rankl, inhibited osteoclast differentiation in vitro and in vivo, and prevented the development of osteolytic lesions in a preclinical metastasis model. We conclude that pathological elevation of miR-218-5p in breast cancer cells activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease, suggesting that miR-218-5p could be an attractive therapeutic target for preventing disease progression.
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    Excess TGF-β mediates muscle weakness associated with bone metastases in mice
    (SpringerNature, 2015-11) Waning, David L.; Mohammad, Khalid S.; Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.
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    Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
    (Biomed Central, 2018-10-04) Petrusca, Daniela N.; Toscani, Denise; Wang, Feng-Ming; Park, Cheolkyu; Crean, Colin D.; Anderson, Judith L.; Marino, Silvia; Mohammad, Khalid S.; Zhou, Dan; Silbermann, Rebecca; Sun, Quanhong; Kurihara, Noriyoshi; Galson, Deborah L.; Giuliani, Nicola; Roodman, G. David; Medicine, School of Medicine
    BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown. METHODS: Human primary CD138+ and BMSC were purified from normal donors and MM patients' bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lentiviral-mediated shRNA. Proliferation/apoptosis studies were done by flow cytometry, and protein levels were determined by Western blot and/or immunohistochemistry. An experimental MM mouse model was generated to investigate the effects of MM cells overexpressing Gfi1 on tumor burden and osteolysis in vivo. RESULTS: We found that Gfi1 expression is increased in patient's MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cells from bortezomib-induced cell death. Gfi1 enhanced cell survival of p53-wt MM cells by binding to p53, thereby blocking binding to the promoters of the pro-apoptotic BAX and NOXA genes. Further, Gfi1-p53 binding could be blocked by HDAC inhibitors. Importantly, inoculation of MM cells overexpressing Gfi1 in mice induced increased bone destruction, increased osteoclast number and size, and enhanced tumor growth. CONCLUSIONS: These results support that Gfi1 plays a key role in MM tumor growth, survival, and bone destruction and contributes to bortezomib resistance, suggesting that Gfi1 may be a novel therapeutic target for MM.
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    High Survivorship With a Titanium-encased Alumina Ceramic Bearing for Total Hip Arthroplasty
    (Springer US, 2014-02) D’Antonio, James A.; Capello, William N.; Naughton, Marybeth; Department of Orthopaedic Surgery, IU School of Medicine
    Background Although ceramic-on-ceramic bearings for total hip arthroplasty (THA) show promising results in terms of bearing-surface wear, fracture of the bearing, insertional chips, and squeaking remain a concern. Questions/purposes Our primary objective of this report was to determine overall survivorship of a titanium- encased ceramic-on-ceramic bearing couple. Our secondary objectives were to evaluate for ceramic fracture, insertional chips, osteolysis, and device squeaking. Methods Six surgeons at six institutions implanted 194 patients (209 hips) with an average age of 52 years with cementless hips and alumina ceramic bearings. One hun- dred thirty-seven patients (146 hips) have 10-year followup (70%). We determined Kaplan-Meier survivorship of the bearing surface and implant system and collected radio- graphic and clinical data to evaluate for osteolysis and squeaking. Results Survivorship using revision for any reason as the end point was 97% at 10 years and survivorship end point bearing surface failure or aseptic loosening of 99%. There was one ceramic insert fracture (0.5%), there were no insertional chips, there was no visible osteolysis on AP and lateral radiographs, and there was a 1% patient- self-reported incidence of squeaking at the last clinical followup. Six hips underwent revision (3.7%). Conclusions Ceramic bearings for THA with a titanium- encased insert have high survivorship at 10 years followup and a fracture risk of 0.5%. We found at last followup on routine radiographs no evidence of osteolysis, and no patient has been revised for squeaking or has reported dissatisfaction with the clinical result because of noise. Level of Evidence Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
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    IL-34 exacerbates pathogenic features of Alzheimer’s disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice
    (Elsevier, 2023) Ho, Anny; Ngala, Bidii; Yamada, Chiaki; Garcia, Christopher; Duarte, Carolina; Akkaoui, Juliet; Ciolac, Dumitru; Nusbaum, Amilia; Kochen, William; Efremova, Daniela; Groppa, Stanislav; Nathanson, Lubov; Bissel, Stephanie; Oblak, Adrian; Kacena, Melissa A.; Movila, Alexandru; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Hallmark features of Alzheimer’s disease (AD) include elevated accumulation of aggregated Aβ40 and Aβ42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aβ40 and Aβ42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.