Stabilization of Beta-Catenin inmTert-Expressing Cells Results in Depletion of Mesenchymal Stem Cells and Bone Loss

2011 ◽  
pp. P1-182-P1-182
Author(s):  
Diana L Carlone ◽  
Rebecca D Riba ◽  
Dana M Ambruzs ◽  
Jessica E Sagers ◽  
David T Breault
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Beta Catenin

Bortezomib Induces Osteoblast Differentiation Via Wnt-Independent Activation of Beta-catenin/TCF Signaling

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 846-846
Author(s):  
Ya-wei Qiang ◽  
Bo Hu ◽  
Yu Chen ◽  
Ying Zhong ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Wnt Signaling ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Receptor Expression ◽  
Calcium Deposition ◽  
Beta Catenin ◽  
Matrix Mineralization

Abstract Bone loss in multiple myeloma (MM) and other conditions represents a serious clinical problem, and extensive research is being conducted to develop new drugs that target signaling cascades whose disruption is known to cause bone loss. Inhibition of Wnt/beta-catenin/TCF signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts. Osteolysis in MM and several other diseases has recently been linked to the suppression of Wnt/beta-catenin/TCF signaling. The antitumor activity of the proteasome inhibitor bortezomib in MM has been linked to its bone anabolic effects. However, the molecular basis of bortezomib’s action on bone is not well characterized. Here we show that bortezomib activates the beta-catenin/TCF pathway in murine and human osteoblast progenitors and human mesenchymal stem cells derived from bone marrow of healthy donors and patients with MM, leading to their subsequent differentiation in-vitro as assessed by matrix mineralization and calcium deposition. Pull-down assays followed by immunoblotting and immunofluorescence microscopy revealed that bortezomib induced stabilization of beta-catenin in both the cytoplasm and nucleus. Nuclear translocation of stabilized beta-catenin was associated with the activation of beta-catenin/TCF transcriptional activity as detected by luciferase activity from TOPFLASH reporter constructs. This activation was not dependent on the drug inducing Wnt ligand or receptor expression, the suppression of Wnt signaling inhibitors or change in disheveled protein levels. Synergy experiments showed that recombinant Wnt3a or LiCl-induced inactivation of GSK3beta did not enhance bortezomib-induced changes in TCF activity. Matrix mineralization was not accompanied by the induction of alkaline phosphatase or osteoprotegerin, which can be activated by Wnt3a in these cell types. Blocking the activation of beta-catenin/TCF signaling by dominant negative TCF attenuated bortezomib-induced matrix mineralization. These results add to the growing body of evidence demonstrating a critical role of the Wnt/beta-catenin pathway in bone biology and provide mechanistic insights into the recently recognized bone anabolic effects of bortezomib. As the effects of bortezomib completely bypass all known regulatory mechanisms governing Wnt signaling, these data also provide a strong rationale for the use of bortezomib in the treatment of diseases linked to suppression of Wnt/beta-catenin signaling.

scholarly journals Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Ning Zhang ◽  
Takeshi Utsunomiya ◽  
Tzuhua Lin ◽  
Yusuke Kohno ◽  
Masaya Ueno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Chronic Inflammation ◽  
Local Injection ◽  
Interleukin 4 ◽  
M2 Macrophage ◽  
Mineral Density ◽  
Primary Surgery ◽  
Polyethylene Particle

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (μCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

BONE CELLS UNDER MICROGRAVITY

2013 ◽  
Vol 13 (05) ◽  
pp. 1340006 ◽  
Author(s):  
PENG SHANG ◽  
JIAN ZHANG ◽  
AIRONG QIAN ◽  
JINGBAO LI ◽  
RUI MENG ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Microgravity Environment ◽  
Human Beings ◽  
Bone Mesenchymal Stem Cells ◽  
Skeleton Structure

Weightlessness environment (also microgravity) during the exploration of space is the major condition which must be faced by astronauts. One of the most serious adverse effects on astronauts is the weightlessness-induced bone loss due to the unbalanced bone remodeling. Bone remodeling of human beings has evolved during billions of years to make bone tissue adapt to the gravitational field of Earth (1g) and maintain skeleton structure to meet mechanical loading on Earth. However, under weightlessness environment the skeleton system no longer functions against the pull of gravity, so there is no necessity to keep bone strong enough to support the body's weight. Therefore, the balance of bone remodeling is disrupted and bone loss occurs, which is extremely deleterious to an astronaut's health during long-term spaceflight. Bone remodeling is mainly orchestrated by bone mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Here, we review how these bone cells respond to microgravity environment.

HIGH GLUCOSE INDUCED BONE LOSS VIA ATTENUATING THE PROLIFERATION AND OSTEOBLASTOGENESIS AND ENHANCING ADIPOGENESIS OF BONE MARROW MESENCHYMAL STEM CELLS

2013 ◽  
Vol 25 (05) ◽  
pp. 1340010 ◽  
Author(s):  
Wen-Tyng Li ◽  
Wen-Kai Hu ◽  
Feng-Ming Ho
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
High Glucose ◽  
Chromatin Condensation ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Bone Marrow Mscs

Diabetes mellitus (DM) is associated with bone loss and leads to osteopenia and osteoporosis. This study was undertaken to investigate whether the impaired functions of mesenchymal stem cells (MSCs) derived from bone marrow play a role in pathogenesis of DM-associated bone loss. Bone marrow MSCs were taken from the alloxan-induced diabetic rats and normal rats. Bone mineral densities of tibias and femurs in diabetic rats decreased compared to those of normal rats as shown by dual energy X-ray absorptiometry. MSCs from diabetic rats exhibited reduced colony formation activity. The in vitro effects of high glucose (HG) (20 or 33 mM) on the growth, oxidative stress, apoptosis, and differentiation MSCs were next assessed. The viability and proliferation of MSCs derived from diabetic rats decreased significantly compared with that from normal rats. HG further suppressed the proliferation and viability of MSCs from both diabetic and normal rats. HG was associated with 38–40% increase in reactive oxygen species level and had significantly downregulated the activities of superoxide dismutase (SOD) and catalase (CAT) which could be recovered by the addition of L-ascorbic acid. The phenomena of apoptosis such as chromatin condensation and DNA fragmentation were found in cells cultured under HG conditions. As compared with 5.5 mM glucose, exposure of MSCs to HG enhanced adipogenic induction of triacylglycerol accumulation and inhibited osteogenic induction of alkaline phosphatase activity. HG increased peroxisome proliferator-activated receptor gamma expression during adipogenesis and reduced RUNX2 expression during osteoblastogenesis. These results indicate that MSCs derived from diabetic rats exhibited the inhibitory effects on cell growth and osteogenic ability. The oxidative stress, apoptosis, and adipogenic capability of MSCs were increased by HG. Furthermore, it is suggested that HG induces bone loss via attenuating the proliferation and osteoblastogenesis and enhancing adipogenesis mediated by the oxidative stress in rat bone marrow MSCs.

scholarly journals Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

2015 ◽  
Vol 195 (11) ◽  
pp. 5136-5148 ◽  
Author(s):  
M. G. Garimella ◽  
S. Kour ◽  
V. Piprode ◽  
M. Mittal ◽  
A. Kumar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Collagen Induced Arthritis ◽  
Systemic Bone Loss

scholarly journals Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

2021 ◽  
Vol 11 ◽  
Author(s):  
Yujue Li ◽  
Lingyun Lu ◽  
Ying Xie ◽  
Xiang Chen ◽  
Li Tian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Interleukin 6 ◽  
High Fat Diet ◽  
Cell Senescence ◽  
Low Grade ◽  
High Fat ◽  
Bone Mesenchymal Stem Cells

Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

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