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Staphylococcus aureus Infects Osteoclasts and Replicates Intracellularly.
Krauss JL, Roper PM, Ballard A, Shih CC, Fitzpatrick JAJ, Cassat JE, Ng PY, Pavlos NJ, Veis DJ
(2019) mBio 10:
MeSH Terms: Animals, Bacterial Proteins, Cell Differentiation, Cells, Cultured, Female, Macrophages, Male, Mice, Osteoblasts, Osteoclasts, Osteomyelitis, Phagosomes, RANK Ligand, Staphylococcus aureus
Show Abstract · Added March 25, 2020
Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by , and even with proper treatment, OM has a high rate of recurrence and chronicity. While has been shown to infect osteoblasts, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. Here, we demonstrate the ability of to intracellularly infect and divide within OCs. OCs were differentiated from bone marrow macrophages (BMMs) by exposure to receptor activator of nuclear factor kappa-B ligand (RANKL). By utilizing an intracellular survival assay and flow cytometry, we found that at 18 h postinfection the intracellular burden of increased dramatically in cells with at least 2 days of RANKL exposure, while the bacterial burden decreased in BMMs. To further explore the signals downstream of RANKL, we manipulated factors controlling OC differentiation, NFATc1 and alternative NF-κB, and found that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal and time-lapse microscopy in mature OCs showed a range of intracellular infection that correlated inversely with -phagolysosome colocalization. The propensity of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing to evade initial immune regulation and proliferate at the periphery of lesions where OCs are most abundant. The inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium To date, the bone-building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone-resorbing cells, osteoclasts, participate. In this study, we show that can infect osteoclasts and proliferate inside these cells, whereas bone-residing macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system.
Copyright © 2019 Krauss et al.
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14 MeSH Terms
Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling.
Mendoza Bertelli A, Delpino MV, Lattar S, Giai C, Llana MN, Sanjuan N, Cassat JE, Sordelli D, Gómez MI
(2016) Biochim Biophys Acta 1862: 1975-83
MeSH Terms: Animals, Cell Differentiation, ErbB Receptors, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Osteoclasts, Osteomyelitis, RANK Ligand, Receptors, Tumor Necrosis Factor, Type I, Staphylococcal Infections, Staphylococcal Protein A, Staphylococcus aureus, Tumor Necrosis Factor-alpha
Added April 3, 2018
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1 Members
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15 MeSH Terms
Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion.
Raghu H, Cruz C, Rewerts CL, Frederick MD, Thornton S, Mullins ES, Schoenecker JG, Degen JL, Flick MJ
(2015) Blood 125: 427-37
MeSH Terms: Animals, Arthritis, Experimental, Blotting, Western, Bone Diseases, Cell Differentiation, Cells, Cultured, Collagen, Factor XIII, Female, Inflammation, Male, Mice, Mice, Inbred DBA, Mice, Knockout, Osteoclasts, RANK Ligand, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration, irreversible cartilage and bone destruction, and exuberant coagulation system activity within joint tissue. Here, we demonstrate that the coagulation transglutaminase, factor XIII (fXIII), drives arthritis pathogenesis by promoting local inflammatory and tissue degradative and remodeling events. All pathological features of collagen-induced arthritis (CIA) were significantly reduced in fXIII-deficient mice. However, the most striking difference in outcome was the preservation of cartilage and bone in fXIIIA(-/-) mice concurrent with reduced osteoclast numbers and activity. The local expression of osteoclast effectors receptor activator of nuclear factor-κB ligand (RANKL) and tartrate resistant acid phosphatase were significantly diminished in CIA-challenged and even unchallenged fXIIIA(-/-) mice relative to wild-type animals, but were similar in wild-type and fibrinogen-deficient mice. Impaired osteoclast formation in fXIIIA(-/-) mice was not due to an inherent deficiency of monocyte precursors, but it was linked to reduced RANKL-driven osteoclast formation. Furthermore, treatment of mice with the pan-transglutaminase inhibitor cystamine resulted in significantly diminished CIA pathology and local markers of osteoclastogenesis. Thus, eliminating fXIIIA limits inflammatory arthritis and protects from cartilage and bone destruction in part through mechanisms linked to reduced RANKL-mediated osteoclastogenesis. In summary, therapeutic strategies targeting fXIII activity may prove beneficial in limiting arthropathies and other degenerative bone diseases.
© 2015 by The American Society of Hematology.
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19 MeSH Terms
Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation.
Johnson RW, White JD, Walker EC, Martin TJ, Sims NA
(2014) Bone 64: 47-56
MeSH Terms: Animals, Cell Differentiation, Cell Line, Chemokines, Ciliary Neurotrophic Factor, Culture Media, Conditioned, Cytokines, Gene Expression, Mice, Mice, Inbred C57BL, Osteoblasts, RANK Ligand, Receptor, Ciliary Neurotrophic Factor
Show Abstract · Added March 26, 2019
Muscle and bone are intimately linked by bi-directional signals regulating both muscle and bone cell gene expression and proliferation. It is generally accepted that muscle cells secrete factors (myokines) that influence adjacent bone cells, but these myokines are yet to be identified. We have previously shown that osteocyte-specific deletion of the co-receptor subunit utilized by IL-6 family cytokines, glycoprotein 130 (gp130), resulted in impaired bone formation in the trabecular bone, but enhanced periosteal expansion, suggesting a gp130-dependent periosteum-specific inhibition of osteoblast function, potentially induced by the local muscle fibres. We report here that differentiated primary calvarial osteoblasts cultured in myotube-conditioned media (CM) from myogenic C2C12 cells show reduced mRNA levels of genes associated with osteoblast differentiation. Alkaline phosphatase protein activity and all mRNA markers of osteoblast differentiation in the tested panel (runx2, osterix, alkaline phosphatase, parathyroid hormone (PTH) receptor, osteoprotegerin, osteocalcin, sclerostin) were reduced following culture with myotube CM. The exception was RANKL, which was significantly elevated in differentiated primary osteoblast cultures expressing osteocytic genes. A cytokine array of the C2C12 myotube-conditioned media identified TIMP-1 and MCP-1 as the most abundant myokines, but treatment with recombinant TIMP-1 or MCP-1 did not inhibit osteoblast gene expression. Rather, the IL-6 family cytokine ciliary neurotrophic factor (CNTF), which we found abundantly expressed by mouse muscle at the transcript and protein level, reduced osteoblast gene expression, although not to the same extent as the myotube-conditioned media. These data indicate that muscle cells secrete abundant TIMP-1, MCP-1, and CNTF, and that of these, only CNTF has the ability to suppress osteoblast function and gene expression in a similar manner to myotube-conditioned medium. This suggests that CNTF is an inhibitory myokine for osteoblasts.
Copyright © 2014 Elsevier Inc. All rights reserved.
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MeSH Terms
Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL.
Ohba T, Cole HA, Cates JM, Slosky DA, Haro H, Ando T, Schwartz HS, Schoenecker JG
(2014) J Bone Miner Res 29: 1431-45
MeSH Terms: Animals, Bone Resorption, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Chemokine CCL2, Diphosphonates, Humans, Imidazoles, Mice, Monocytes, Neoplasm Invasiveness, Osteoclasts, Osteogenesis, Osteolysis, Osteoprotegerin, Osteosarcoma, RANK Ligand, Zoledronic Acid
Show Abstract · Added March 20, 2014
Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor-induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. However, the molecular mechanisms responsible for, and means of inhibiting, osteosarcoma-induced osteolysis are largely unknown. We establish that osteosarcoma growth directly correlates with tumor-induced osteolysis and activation of osteoclasts in vivo. In vitro, tumor cells were determined to expresses surface, but not soluble, receptor activator of NF-κB ligand (RANKL) and stimulated osteoclastogenesis in a manner directly proportional to their malignant potential. In addition, an aggressive osteosarcoma cell line was shown to secrete monocyte chemoattractant protein-1 (MCP-1), resulting in robust monocyte migration. Because MCP-1 is a key cytokine for monocyte recruitment and surface-bound RANKL strongly supports local osteoclastogenesis, we suggest that high levels of these signaling molecules are associated with the aggressive potential of osteosarcoma. Consistent with these findings, abundant expression of RANKL/MCP-1 was observed in tumor in vivo, and MCP-1 plasma levels strongly correlated with tumor progression and osteolysis. ZOL administration directly attenuates osteosarcoma production of RANKL/MCP-1, reducing tumor-induced bone destruction. In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor-induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans.
© 2014 American Society for Bone and Mineral Research.
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19 MeSH Terms
Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.
Rana T, Schultz MA, Freeman ML, Biswas S
(2012) Free Radic Biol Med 53: 2298-307
MeSH Terms: Animals, Bone Marrow Cells, Cell Survival, Mice, Mice, Knockout, NF-E2-Related Factor 2, Osteoblasts, Osteoclasts, Osteoporosis, Oxidative Stress, RANK Ligand, Radiation Injuries, Experimental, Radiation Tolerance, Skull, Tibia, Up-Regulation
Show Abstract · Added March 13, 2014
Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20Gy) the hindlegs of age- and sex-matched Nrf2(+/+) and Nrf2(-/-) mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2(-/-) mice compared to Nrf2(+/+) mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss.
Copyright © 2012 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Choosing a treatment for patients at the time a fracture is presented.
Tanner SB
(2011) Curr Osteoporos Rep 9: 156-9
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Denosumab, Diphosphonates, Fractures, Spontaneous, Humans, Osteoporosis, RANK Ligand, Secondary Prevention, Teriparatide
Show Abstract · Added January 20, 2015
The occurrence of a fragility fracture is an opportunity to recognize osteoporosis and begin treatment to reduce the risk of another fracture. However, selecting the treatment may have an impact on the incident fracture and this requires careful consideration of the patient and the treatment choices. There is no consensus regarding the management of osteoporosis at the time of an incident fracture. This review will consider the treatment options after a fragility fracture.
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10 MeSH Terms
Bone structural components regulating sites of tumor metastasis.
Sterling JA, Guelcher SA
(2011) Curr Osteoporos Rep 9: 89-95
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bone Density Conservation Agents, Bone Neoplasms, Breast Neoplasms, Denosumab, Diphosphonates, Female, Humans, Kruppel-Like Transcription Factors, Male, Nuclear Proteins, Parathyroid Hormone-Related Protein, RANK Ligand, Transforming Growth Factor beta, Zinc Finger Protein Gli2, rho-Associated Kinases
Show Abstract · Added March 5, 2014
Tumors such as breast, lung, and prostate frequently metastasize to bone, where they can cause intractable pain and increase the risk of fracture in patients. When tumor cells metastasize to bone, they interact with the microenvironment to promote bone destruction primarily through the secretion of osteolytic factors by the tumor cells and the subsequent release of growth factors from the bone. Our recent data suggest that the differential rigidity of the mineralized bone microenvironment relative to that of soft tissue regulates the expression of osteolytic factors by the tumor cells. The concept that matrix rigidity regulates tumor growth is well established in solid breast tumors, where increased rigidity stimulates tumor cell invasion and metastasis. Our studies have indicated that a transforming growth factor-β (TGF-β) and Rho-associated kinase (ROCK)-dependent mechanism is involved in the response of metastatic tumor cells to the rigid mineralized bone matrix. In this review, we will discuss the interactions between ROCK and TGF-β signaling, as well as potential new therapies that target these pathways.
1 Communities
2 Members
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17 MeSH Terms
Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.
Thiolloy S, Halpern J, Holt GE, Schwartz HS, Mundy GR, Matrisian LM, Lynch CC
(2009) Cancer Res 69: 6747-55
MeSH Terms: Animals, Bone Density, Bone Neoplasms, Breast Neoplasms, Cell Proliferation, Cells, Cultured, Female, Humans, Matrix Metalloproteinase 7, Matrix Metalloproteinase 9, Mice, Mice, Knockout, Osteoclasts, Osteolysis, RANK Ligand, Tumor Burden
Show Abstract · Added March 5, 2014
The matrix metalloproteinases MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in the tumor-bone microenvironment, and, of these, MMP-7 and MMP-9 were found to be localized to bone-resorbing osteoclasts in human breast-to-bone metastases. In a bid to define the roles of host-derived MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibias of MMP-7 and MMP-9 null mice were injected with osteolytic luciferase-tagged mammary tumor cell lines. Our data show that osteoclast-derived MMP-7 significantly contributes to tumor growth and tumor-induced osteolysis whereas osteoclast-derived MMP-9 had no effect on these processes. MMP-7 is capable of processing a number of nonmatrix molecules to soluble active forms that have profound effects on cell-cell communication, such as RANKL, a crucial mediator of osteoclast precursor recruitment and maturation. Therefore, the ability of osteoclast-derived MMP-7 to promote RANKL solubilization in the tumor-bone microenvironment was explored. Results revealed that levels of soluble RANKL were significantly lower in the MMP-7 null mice compared with wild-type (WT) controls. In keeping with this observation, MMP-7 null mice had significantly fewer osteoclast numbers at the tumor-bone interface compared with the WT controls. In summary, we propose that the solubilization of RANKL by MMP-7 is a potential mechanism through which MMP-7 mediates mammary tumor-induced osteolysis. Our studies indicate that the selective inhibition of MMP-7 in the tumor-bone microenvironment may be of benefit for the treatment of lytic breast-to-bone metastases.
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16 MeSH Terms
Hedgehog coordination of postnatal osteoclast and osteoblast activities.
Mundy GR, Yang X
(2008) Dev Cell 14: 637-8
MeSH Terms: Animals, Animals, Newborn, Humans, Mice, Organ Size, Osteoblasts, Osteoclasts, Osteogenesis, Parathyroid Hormone-Related Protein, Patched Receptors, RANK Ligand, Receptors, Cell Surface, Signal Transduction
Show Abstract · Added May 28, 2014
The Hedgehog (Hh) pathway is important for skeletal patterning and morphogenesis during embryonic development. Papers by Ohba et al. and Mak et al. in this edition of Developmental Cell suggest that Hh signaling may exert delicate control over the activities of osteoclasts and osteoblasts, the cell types primarily responsible for bone resorption and formation.
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13 MeSH Terms