Vanderbilt Center for Bone Biology

Nashville, TN, United States

Vanderbilt Center for Bone Biology

Nashville, TN, United States
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Hansen A.G.,Vanderbilt University | Arnold S.A.,Vanderbilt University | Jiang M.,Urologic | Jiang M.,Nantong University | And 10 more authors.
Cancer Research | Year: 2014

The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies, we demonstrate that the cell adhesion molecule, activated leukocyte cell adhesion molecule (ALCAM), is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGF-b. Not only is this posttranslational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveals that ALCAM expression and shedding is elevated in response to TGF-b signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (caspase-3) and decreased proliferation (Ki67). Together, these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression. © 2013 American Association for Cancer Research.


Sterling J.A.,Vanderbilt Center for Bone Biology | Sterling J.A.,Vanderbilt University
Cancer Discovery | Year: 2015

The recent article by Junankar and colleagues focuses on demonstrating the uptake of bisphosphonates (BP) into the primary tumor in both animal models and human samples. Interestingly, the authors were able to establish tumor-associated macrophages as the cell type that takes up the BPs. These studies are an important advancement for understanding the potential benefits of using BPs as adjuvant therapy in patients with cancer. © 2015 American Association for Cancer Research.


Hiraga T.,Osaka University | Hiraga T.,Matsumoto Dental University | Myoui A.,Osaka University | Hashimoto N.,Osaka University | And 9 more authors.
Cancer Research | Year: 2012

The continuous release of bone-stored growth factors after bone resorption promotes the colonization of circulating cancer cells. However, the precise role of each of the various growth factors remains unclear. In this study, we investigated the role of bone-derived insulin-like growth factor (IGF) in the development of bone metastases in an animal model of breast cancer. We found that local stimulation of calvarial bone resorption before cell inoculation stimulated subsequent bone metastases to that site in vivo, although inhibition of bone resorption inhibited bone metastases. Anchorage-independent growth of cancer cells was stimulated by the culture supernatants from resorbed bones, which contained elevated levels of IGF-I. This stimulation was blocked by IGF type I receptor (IGF-IR) neutralizing antibody, but not antibody targeting other bone-stored growth factors including TGF-β, fibroblast growth factors, and platelet-derived growth factors. Although recombinant human IGF-I caused IGF-IR tyrosine autophosphorylation, followed by activation of Akt and NF-κB in cancer cells, dominant-negative inhibition of IGF-IR, Akt, or NF-κB significantly reduced bone metastases with increased apoptosis and decreased mitosis in metastatic cells. Together, our findings suggest that bone-derived IGF-I bridges the crosstalk between bone and metastasized cancer cells via activation of the IGF-IR/Akt/NF-κB pathway. Disruption of this pathway therefore may represent a promising therapeutic intervention for bone metastasis. © 2012 AACR.


Danilin S.,Vanderbilt Center for Bone Biology | Danilin S.,University of Strasbourg | Merkel A.R.,Vanderbilt Center for Bone Biology | Johnson J.R.,Vanderbilt Center for Bone Biology | And 5 more authors.
OncoImmunology | Year: 2012

Myeloid-derived suppressor cells (MDSC s), identified as Gr1+CD11b+ cells in mice, expand duringcancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSC s may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSC s expansion by fluorescence-activated cell sorting. To explore the contribution of MDSC s to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1+CD11b+ cells isolated from healthy or tumor-bearing mice into the left tibia. MDSC s didn't induce bone resorption in normal mice, but increased resorptionand tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1+CD11b+ cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANKligand and macrophage colony-stimulating factor, and that MDSC s from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor β expression that we observed in MDSC s isolated from tumor-bearing mice. Importantly, using MDSC s isolated from GFP-expressing animals, we foundthat MDSC s differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP+TRAP+ cells. These results demonstrate that MDSC s expand in breast cancer bone metastasesand induce bone destruction. Furthermore, our data strongly suggest that MDSC s are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors. © 2012 Landes Bioscience.


Sant D.W.,Arup | Margraf R.L.,Arup | Stevenson D.A.,University of Utah | Grossmann A.H.,University of Utah | And 7 more authors.
Journal of Medical Genetics | Year: 2015

Background Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the 'second hit' mutation remains unclear. Methods Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline (peripheral blood). Results A germline NF1 splice site mutation (c.61-2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown. Conclusions Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes. © 2015 by the BMJ Publishing Group Ltd.


Anbinder A.L.,São Paulo State University | Moraes R.M.,São Paulo State University | Lima G.M.G.,São Paulo State University | Oliveira F.E.,São Paulo State University | And 7 more authors.
Bone | Year: 2016

Periodontal pathogens and/or inflammatory products from periodontitis participate in the development or progression of systemic diseases. In this context, periodontitis acts as a modifying factor to systemic health, including diabetes and cardiovascular diseases. Osteoporosis is an increasingly prevalent condition in our aging population and considered a risk factor for periodontal disease, but the effect of periodontitis on systemic bone homeostasis is unknown. We thus evaluated the effects of experimental periodontitis (EP) on systemic bone loss and the influence of estrogen deficiency in this context, using a mouse model of combined periodontitis and osteoporosis. Experimental periodontitis (EP) was induced by a ligature insertion around the mandibular first molars and Porphyromonas gingivalis infection. Three-dimensional microcomputed tomographic analyses performed 48 days following infection revealed that EP and ovariectomy (OVX) induced a significantly higher femoral and mandibular bone loss compared to EP or OVX alone. EP alone did not induce systemic bone loss. In addition, the EP. +. OVX and EP groups showed significantly higher levels of tumor necrosis factor (TNF)-α than OVX and control groups at end point. These results suggest that periodontitis could be a risk factor for systemic bone loss, especially in post-menopausal women, and warrant further clinical investigations to confirm this association and propose adapted prophylactic and curative therapies. © 2015 Elsevier Inc.


PubMed | Vanderbilt Center for Bone Biology
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2012

ATF4 is an osteoblast-enriched transcription factor of the leucine zipper family. We recently identified that vimentin, a leucine zipper-containing intermediate filament protein, suppresses ATF4-dependent osteocalcin (Ocn) transcription and osteoblast differentiation. Here we show that TGF inhibits ATF4-dependent activation of Ocn by up-regulation of vimentin expression. Osteoblasts lacking Atf4 (Atf4(-/-)) were less sensitive than wild-type (WT) cells to the inhibition by TGF on alkaline phosphatase activity, Ocn transcription and mineralization. Importantly, the anabolic effect of a monoclonal antibody neutralizing active TGF ligands on bone in WT mice was blunted in Atf4(-/-) mice. These data establish that ATF4 is required for TGF-related suppression of Ocn transcription and osteoblast differentiation in vitro and in vivo. Interestingly, TGF did not directly regulate the expression of ATF4; instead, it enhanced the expression of vimentin, a negative regulator of ATF4, at the post-transcriptional level. Accordingly, knockdown of endogenous vimentin in 2T3 osteoblasts abolished the inhibition of Ocn transcription by TGF, confirming an indirect mechanism by which TGF acts through vimentin to suppress ATF4-dependent Ocn activation. Furthermore, inhibition of PI3K/Akt/mTOR signaling, but not canonical Smad signaling, downstream of TGF, blocked TGF-induced synthesis of vimentin, and inhibited ATF4-dependent Ocn transcription in osteoblasts. Thus, our study identifies that TGF stimulates vimentin production via PI3K-Akt-mTOR signaling, which leads to suppression of ATF4-dependent Ocn transcription and osteoblast differentiation.

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