Constitutively Active Canonical NF-κB Pathway Induces Severe Bone Loss in Mice

Otero, Jesse E.; Chen, Timothy; Zhang, Kaihua; Abu‐Amer, Yousef

doi:10.1371/journal.pone.0038694

Cited by 29 publications

(28 citation statements)

References 25 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: 69%

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: 69%

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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“…The Role of Cytokines in Inflammatory Bone Loss expression of constitutively active IKKb in Cd11b þ myeloid cells generates mice which exhibited decreased bone mass in trabecular bone due to increased number of osteoclasts on the trabecular bone surfaces (Otero et al, 2012a). For reasons not understood, no such changes were seen in cortical bone.…”

Section: Rankmentioning

confidence: 99%

The role of cytokines in inflammatory bone loss

Souza

Lerner

2013

Immunological Investigations

225

231

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Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro- and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.

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“…The physiological relevance of this finding was demonstrated in vivo using a myeloid knock-in of the transgene IKK2SSEE. Phenotypic assessment revealed that expression of IKK2SSEE in the myeloid compartment induced significant bone loss in vivo [38], manifested by significant increase in the number and size of osteoclasts in trabecular regions, elevated levels of circulating TRACP-5b, and reduced bone volume. Mechanistically, IKK2SSEE induced high expression of not only p65/RelA but also p52 and RelB; the latter two molecules are considered exclusive members of the alternative NF-κB pathway.…”

Section: Role Of Individual Nf-κb Subunits and Kinases In Osteoclastsmentioning

confidence: 99%

NF-κB signaling and bone resorption

2013

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The transcription factor NF-κB is a family of proteins involved in signaling pathways essential for normal cellular functions and development. Deletion of various components of this pathway resulted with abnormal skeletal development. Research in the last decade has established that NF-κB signaling mediates RANK ligand-induced osteoclastogenesis. Consistently, it was shown that inhibition of NF-κB was an effective approach to inhibit osteoclast formation and bone resorptive activity. Identification of the molecular machinery underlying NF-κB activation permitted osteoclast-specific deletion of the major components of this pathway. As a result, it was clear that deletion of members of the proximal IKK kinase complex and the distal NF-κB subunits and downstream regulators affected skeletal development. These studies provided several targets of therapeutic intervention in osteolytic diseases. NF-κB activity has been also described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. Indeed, inflammatory insults exacerbate physiologic RANKL-induced NF-κB signals leading to exaggerated responses and to inflammatory osteolysis. These superimposed NF-κB activities appear to underlie several bone pathologies. This review will describe the individual roles of NF-κB molecules in bone resorption and inflammatory osteolysis.

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Constitutively Active Canonical NF-κB Pathway Induces Severe Bone Loss in Mice

Cited by 29 publications

References 25 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 role of cytokines in inflammatory bone loss

NF-κB signaling and bone resorption

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