scholarly journals Bone Marrow Derived Extracellular Vesicles Activate Osteoclast Differentiation in Traumatic Brain Injury Induced Bone Loss

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 63 ◽  
Author(s):  
Quante Singleton ◽  
Kumar Vaibhav ◽  
Molly Braun ◽  
Chandani Patel ◽  
Andrew Khayrullin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Bone Loss ◽  
Extracellular Vesicles ◽  
Bone Fractures ◽  
Ex Vivo ◽  
Osteoclast Differentiation ◽  
Bone Marrow Niche ◽  
Bone Marrow Derived Cells

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in vivo CD-1 mice. Further, we identified dysregulated NF-κB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

scholarly journals Bone marrow derived extracellular vesicles activate osteoclast differentiation in traumatic brain injury induced bone loss

2018 ◽  
Author(s):  
Quante Singleton ◽  
Kumar Vaibhav ◽  
Molly Braun ◽  
Andrew Khayrullin ◽  
Bharati Mendhe ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Bone Loss ◽  
Extracellular Vesicles ◽  
Bone Marrow Cells ◽  
Bone Fractures ◽  
Osteoclast Differentiation ◽  
Bone Marrow Niche ◽  
Bone Marrow Derived Cells

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

scholarly journals Realization of Osteolysis, Angiogenesis, Immunosuppression, and Drug Resistance by Extracellular Vesicles: Roles of RNAs and Proteins in Their Cargoes and of Ectonucleotidases of the Immunosuppressive Adenosinergic Noncanonical Pathway in the Bone Marrow Niche of Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2969
Author(s):  
Takashi Watanabe
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cell ◽  
Extracellular Vesicles ◽  
Osteoclast Differentiation ◽  
Suppressor Cell ◽  
Myeloma Cell ◽  
Bone Marrow Niche ◽  
Myeloma Cells

Angiogenesis and immunosuppression promote multiple myeloma (MM) development, and osteolysis is a primary feature of MM. Although immunomodulatory drugs and proteasome inhibitors (PIs) markedly improve the survival of patients with MM, this disease remains incurable. In the bone marrow niche, a chain of ectoenzymes, including CD38, produce immunosuppressive adenosine, inhibiting T cell proliferation as well as immunosuppressive cells. Therefore, anti-CD38 antibodies targeting myeloma cells have the potential to restore T cell responses to myeloma cells. Meanwhile extracellular vesicles (EVs) containing microRNAs, proteins such as cytokines and chemokines, long noncoding RNAs, and PIWI-interacting RNAs have been shown to act as communication tools in myeloma cell/microenvironment interactions. Via EVs, mesenchymal stem cells allow myeloma cell dissemination and confer PI resistance, whereas myeloma cells promote angiogenesis, myeloid-derived suppressor cell proliferation, and osteoclast differentiation and inhibit osteoblast differentiation. In this review, to understand key processes of MM development involving communication between myeloma cells and other cells in the tumor microenvironment, EV cargo and the non-canonical adenosinergic pathway are introduced, and ectoenzymes and EVs are discussed as potential druggable targets for the treatment of MM patients.

scholarly journals GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jin-Ran Chen ◽  
Haijun Zhao ◽  
Umesh D. Wankhade ◽  
Sree V. Chintapalli ◽  
Can Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Hippuric Acid ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Wild Type ◽  
Osteoclast Precursors

AbstractThe G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A−/−) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A−/− mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A−/− mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A−/− mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/β-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/β-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A−/− mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.

scholarly journals Bone Marrow Stromal Cells Promote Neuronal Restoration in Rats with Traumatic Brain Injury: Involvement of GDNF Regulating BAD and BAX Signaling

2016 ◽  
Vol 38 (2) ◽  
pp. 748-762 ◽  
Author(s):  
Qin Shen ◽  
Yong Yin ◽  
Qing-Jie Xia ◽  
Na Lin ◽  
You-Cui Wang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Fluorescent Protein ◽  
Neurological Function ◽  
Marrow Stromal Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Green Fluorescent

Background/Aims: To investigate the effects of bone marrow stromal cells (BMSCs) and underlying mechanisms in traumatic brain injury (TBI). Methods: Cultured BMSCs from green fluorescent protein-transgenic mice were isolated and confirmed. Cultured BMSCs were immediately transplanted into the regions surrounding the injured-brain site to test their function in rat models of TBI. Neurological function was evaluated by a modified neurological severity score on the day before, and on days 7 and 14 after transplantation. After 2 weeks of BMSC transplantation, the brain tissue was harvested and analyzed by microarray assay. And the coronal brain sections were determined by immunohistochemistry with mouse anti-growth-associated protein-43 kDa (anti-GAP-43) and anti-synaptophysin to test the effects of transplanted cells on the axonal regeneration in the host brain. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and Western blot were used to detect the apoptosis and expression of BAX and BAD. Results: Microarray analysis showed that BMSCs expressed growth factors such as glial cell-line derived neurotrophic factor (GDNF). The cells migrated around the injury sites in rats with TBI. BMSC grafts resulted in an increased number of GAP-43-immunopositive fibers and synaptophysin-positive varicosity, with suppressed apoptosis. Furthermore, BMSC transplantation significantly downregulated the expression of BAX and BAD signaling. Moreover, cultured BMSC transplantation significantly improved rat neurological function and survival. Conclusion: Transplanted BMSCs could survive and improve neuronal behavior in rats with TBI. Mechanisms of neuroprotection and regeneration were involved, which could be associated with the GDNF regulating the apoptosis signals through BAX and BAD.

scholarly journals Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles

2019 ◽  
Vol 234 (8) ◽  
pp. 14377-14388 ◽  
Author(s):  
Yan Cheng ◽  
Mandy Pereira ◽  
Neha Raukar ◽  
John L. Reagan ◽  
Mathew Queseneberry ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Extracellular Vesicles ◽  
Potential Biomarkers

Ostericum koreanum Reduces LPS-Induced Bone Loss Through Inhibition of Osteoclastogenesis

2015 ◽  
Vol 43 (03) ◽  
pp. 495-512 ◽  
Author(s):  
Ju-Young Kim ◽  
Sung-Jun Ahn ◽  
Jong Min Baek ◽  
Kwon-Ha Yoon ◽  
Myeung Su Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Bone Structure ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Therapeutic Drug ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mouse Bone Marrow ◽  
Actin Ring ◽  
Ostericum Koreanum

The roots of Ostericum koreanum (OK) Maximowicz have traditionally been used to produce an herbal medicine reported to possess anti-inflammatory, anti-oxidant, antimicrobial, and antitumor activities; however, its effect on bone metabolism has not yet been reported. The present study examined the effects of OK extract on lipopolysaccharide (LPS)-induced bone loss in mice by investigating bone structure and the levels of the receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in serum and bone marrow fluid (BMF). The effects of OK extract on osteoclastogenesis were also investigated in mouse bone marrow macrophages by examining the formation of tartrate-resistant acid phosphatase (TRAP)-positive cells, the actin ring, and bone resorption activity. OK reduced LPS-induced bone destruction in vivo via a decrease in the RANKL/OPG ratio. Furthermore, it suppressed the formation of TRAP-positive cells and the actin ring, and reduced the bone-resorbing activity of mature osteoclasts. OK also significantly down-regulated the expression of various osteoclast-specific genes. However, it did not affect osteoblast differentiation, or the expression of genes involved in this process. These results demonstrated that OK prevented LPS-induced bone loss by decreasing the RANKL/OPG ratio in serum and BMF, and inhibited osteoclast differentiation and function, suggesting that OK represents a potential therapeutic drug for the treatment of osteoclast-associated bone diseases.

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