Disruption of NF-κB1 prevents bone loss caused by mechanical unloading

Nakamura, Hitomi; Aoki, Kazuhiro; Masuda, Wataru; Alles, Neil; Nagano, Kenichi; Fukushima, Hidefumi; Osawa, Kenji; Yasuda, Hisataka; Nakamura, Ichiro; Mikuni-Takagaki, Yuko; Ohya, Keiichi; Maki, Kenshi; Jimi, Eijiro

doi:10.1002/jbmr.1866

Cited by 37 publications

(24 citation statements)

References 34 publications

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“…30 Previous reports suggested that TNF-a enhances osteoclastogenesis and inhibits osteogenesis at an early stage of inflammation, but induces osteogenesis at the later tissue repair stages of inflammation. 30 The role of NF-kB in osteogenesis in previous reports [31][32][33][34][35] and our current findings may be due to different time points of evaluation, different proinflammatory stimuli, and the specific osteogenic markers tested.…”

Section: Figmentioning

confidence: 68%

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

Lin

Sato

Barcay

et al. 2015

Tissue Engineering Part A

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Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-kB in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultrahigh-molecular-weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF-kB signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased transforming growth factor-beta 1 (TGF-b1) and osteoprotegerin (OPG) in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN upregulated OPG expression through a TGFb1-dependent pathway. By measuring the alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regard to cell phenotype, cell viability, and osteogenic ability was confirmed using primary human MSCs. Our results suggest that modulation of wear particle-induced inflammation by NF-kB decoy ODN had no adverse effects on MSCs and may potentially further mitigate periprosthetic osteolysis by protecting MSC viability and osteogenic ability.

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Section: Figmentioning

confidence: 68%

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

Lin

Sato

Barcay

et al. 2015

Tissue Engineering Part A

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“…22,25,26 Qualitative analysis demonstrated an increase in cytoplasmic staining of both NF-κB and p-NF-κB in burn plus tenotomy versus tenotomy alone at 5 days after injury (Fig. 5, above and center ).…”

Section: Resultsmentioning

confidence: 96%

“…7,35,36 NF-κB has been linked to a systemic rise in TNF-α following burn injury. 25,26 Similarly, NF-κB mediates protein loss induced by TNF-α in differentiated skeletal muscle myotubes, and is up-regulated in multiple models of atrophy, which include sepsis, burn, malignancy, and skeletal muscle unloading. 22 Transgenic mice using knockout of the p105/p50 NF-κB1 gene demonstrated decreased muscle atrophy in NF-κB (−/−) mice compared with wild type.…”

Section: Discussionmentioning

confidence: 99%

The Systemic Effect of Burn Injury and Trauma on Muscle and Bone Mass and Composition

Rinkinen

Hwang

Agarwal

et al. 2015

Plastic and Reconstructive Surgery

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Background By understanding the global inflammatory effects on distant myopathies, surgeons can better guide the rehabilitative process for burn patients. The authors tested the systemic effect of burn injury on distant injured muscle and native bone using immunohistochemistry and validated a new morphometric analytic modality to reproducibly quantify muscle atrophy using computed tomographic imaging. Methods In vivo studies were performed on C57/BL6 mice using an Achilles tenotomy with concurrent burn injury model. Total muscle and bone (tibia and fibula) volume/density were quantified near the site of Achilles tenotomy using micro–computed tomography at 5, 7, and 9 to 12 weeks after surgery. The impact of burn injury on the inflammatory cascade [nuclear factor (NF)-κB, p-NF-κB] and the interconnected protein catabolism signaling pathway (Atrogin-1) was assessed by immunohistochemistry. Results Muscle volume and density at the site of Achilles tenotomy in burned mice were significantly diminished compared with nonburned mice at 5 weeks and 9 to 12 weeks. Similar decreases in muscle volume and density were observed when comparing tenotomy to no tenotomy. Cortical bone health remained stable in burn/tenotomy mice compared with tenotomy. Muscle atrophy was associated with up-regulation of p-NF-κB, NF-κB, and Atrogin-1 assessed by immunohistochemistry. Conclusions Burn injury significantly decreases muscle volume and density. Increased muscle atrophy using our computed tomographic morphometric analysis correlated with a significant increase in intramuscular inflammatory markers and proteolysis enzymes. This study demonstrates a unique characterization of how burn injuries may worsen local myopathy. Moreover, it provides a novel approach for quantifying muscle atrophy over an expanded period.

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“…77 NF-kB1 plays a central role in bone reduction under microgravity conditions. 78 Clejan et al showed that the activation of apoptotic pathways during an early phase of culturing DU-145 human prostate carcinoma cells in a HARV is essential for the subsequent formation of 3D organoids. 79 Our experiments on the RPM on FTC-133 thyroid cancer cells suggested that initiation of an early phase of apoptosis, followed by an escape from the late phase, could be a step in cells that transit from a 2D to a 3D kind of growth.…”

Section: Known Mechanisms Involved In Spheroid Formationmentioning

confidence: 99%

Growing Tissues in Real and Simulated Microgravity: New Methods for Tissue Engineering

Grimm

Wehland

Pietsch

et al. 2014

Tissue Engineering Part B: Reviews

121

137

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Tissue engineering in simulated (s-) and real microgravity (r-mg) is currently a topic in Space medicine contributing to biomedical sciences and their applications on Earth. The principal aim of this review is to highlight the advances and accomplishments in the field of tissue engineering that could be achieved by culturing cells in Space or by devices created to simulate microgravity on Earth. Understanding the biology of three-dimensional (3D) multicellular structures is very important for a more complete appreciation of in vivo tissue function and advancing in vitro tissue engineering efforts. Various cells exposed to r-mg in Space or to s-mg created by a random positioning machine, a 2D-clinostat, or a rotating wall vessel bioreactor grew in the form of 3D tissues. Hence, these methods represent a new strategy for tissue engineering of a variety of tissues, such as regenerated cartilage, artificial vessel constructs, and other organ tissues as well as multicellular cancer spheroids. These aggregates are used to study molecular mechanisms involved in angiogenesis, cancer development, and biology and for pharmacological testing of, for example, chemotherapeutic drugs or inhibitors of neoangiogenesis. Moreover, they are useful for studying multicellular responses in toxicology and radiation biology, or for performing coculture experiments. The future will show whether these tissue-engineered constructs can be used for medical transplantations. Unveiling the mechanisms of microgravity-dependent molecular and cellular changes is an up-to-date requirement for improving Space medicine and developing new treatment strategies that can be translated to in vivo models while reducing the use of laboratory animals.

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Disruption of NF-κB1 prevents bone loss caused by mechanical unloading

Cited by 37 publications

References 34 publications

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

The Systemic Effect of Burn Injury and Trauma on Muscle and Bone Mass and Composition

Growing Tissues in Real and Simulated Microgravity: New Methods for Tissue Engineering

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