Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway.

Rezaee, Fariba; Rellick, SL; Akers, SM; O’Leary, Heather A.; Piedimonte, Giovanni; Lf, Gibson

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2860

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…Consistent with this hypothesis are the results of Rezaee et al . who reported that neurotrophins stimulate BM stromal cell to secrete IL‐6, a factor recently identified to be involved in myeloma‐induced RANKL expression in T lymphocytes by Giuliani et al . Combined with our previous data that BDNFs are correlated with MIP‐1α, and β2‐microglobulin levels in patients with active myeloma, these data suggest that the complex interaction between BDNF and other OAFs in BM appears to be responsible in part for myeloma bone disease.…”

Section: Discussionsupporting

confidence: 79%

Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo

Sun

Wang

et al. 2013

Intl Journal of Cancer

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Osteolytic bone diseases are a prominent feature of multiple myeloma (MM), resulting from aberrant osteoclastic bone resorption that is uncoupled from osteoblastic bone formation. Myeloma stimulates osteoclastogenesis, which is largely dependent on an increase in receptor activator of NF-jB ligand (RANKL) and a decrease in osteoprotegerin (OPG) within the bone marrow milieu. Recently, brain-derived neurotrophic factor (BDNF) was identified as a MM-derived factor that correlates with increased RANKL levels and contributes to osteolytic bone destruction in myeloma patients. Because tyrosine receptor kinase B (TrkB), the receptor of BDNF, is abundantly expressed in osteoblasts, we sought to evaluate the role of BDNF/TrkB in myeloma-osteoblast interactions and the effect of this pathway on the RANKL/OPG ratio and osteoclastogenesis. Coculture systems constructed with noncontact transwells revealed that, in vitro, MM-derived BDNF increased RANKL and decreased OPG production in osteoblasts in a time-and dose-dependent manner. These effects were completely abolished by a specific small interfering RNA for TrkB. BDNF regulates RANKL/OPG expression in osteoblasts through the TrkB/ERK pathway. To investigate the biological effects of BDNF on myeloma in vivo, a SCID-RPMI8226 mice model was constructed using lentiviral short hairpin RNAtransfected RPMI8226 cells. In this system, stable knockdown of BDNF in MM cells significantly restored the RANKL/OPG homostasis, inhibited osteolytic bone destruction and reduced angiogenesis and tumor burden. Our studies provide further support for the potential osteoclastogenic effects of BDNF, which mediates stroma-myeloma interactions to disrupt the balance of RANKL/OPG expression, ultimately increasing osteoclastogenesis in MM.Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of plasma cells within the bone marrow (BM). Bone destruction is the most common feature of MM, which results from the deregulation of osteoclast and osteoblast activities adjacent to myeloma cells.1 Signs of skeleton involvement in MM include osteolytic bone lesions, spine compression and fractures, which significantly impact morbidity and mortality. A variety of MM-derived factors that stimulate osteoclast formation and activity, either directly or indirectly, has been identified. These osteoclast-activating factors (OAFs) include interleukin-1b (IL-1b), interleukin-11 (IL-11), tumor necrosis factor-1b (TNF-1b), hepatocyte growth factor (HGF), stromal-derived factor-1a (SDF-1a), RANKL and the more recently identified macrophage inflammatory protein-1a (MIP-1a).2-6 Among all these factors, RANKL plays a predominate role. 7 Osteoclasts are activated by binding of RANKL to its cognate receptor, RANK, whereas osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor family, acts as a nonfunctional decoy receptor to compete with RANK and inhibits the terminal stages of osteoclast differentiation and activation. 8Mice deficient in OPG showed severe osteoporosis, 9,10 where...

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Section: Discussionsupporting

confidence: 79%

Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo

Sun

Wang

et al. 2013

Intl Journal of Cancer

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“…Although mechanisms underlying their regulatory action in osteogenic process have not been completely elucidated, recent studies showed that many mediators of the inflammatory response play a key role in osteogenesis. Among DEG, a set of genes known to be involved both in inflammation and bone formation appears, which includes: IL6, encoding a cytokine that acts in the maturation of B cells, is known to be an important pro-inflammatory cytokine secreted by osteoblasts in bone resorption process [ 73 ], and in human BMSCs it seems to positively influence the mitogen-activated protein kinase signaling cascade, essential for normal skeletogenesis and bone formation [ 74 ]; the protein encoded by PTGES gene, a glutathione-dependent prostaglandin E synthase, was evidenced in the monolayered MSCs [ 75 ] and several studies suggest this gene contributing to decrease cell proliferation and induces osteogenesis [ 76 ]; IL1, an heterodimer containing α and β subunits, seems to intervene in bone remodeling process [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

Osteogenic Differentiation of MSC through Calcium Signaling Activation: Transcriptomics and Functional Analysis

et al. 2016

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The culture of progenitor mesenchymal stem cells (MSC) onto osteoconductive materials to induce a proper osteogenic differentiation and mineralized matrix regeneration represents a promising and widely diffused experimental approach for tissue-engineering (TE) applications in orthopaedics. Among modern biomaterials, calcium phosphates represent the best bone substitutes, due to their chemical features emulating the mineral phase of bone tissue. Although many studies on stem cells differentiation mechanisms have been performed involving calcium-based scaffolds, results often focus on highlighting production of in vitro bone matrix markers and in vivo tissue ingrowth, while information related to the biomolecular mechanisms involved in the early cellular calcium-mediated differentiation is not well elucidated yet. Genetic programs for osteogenesis have been just partially deciphered, and the description of the different molecules and pathways operative in these differentiations is far from complete, as well as the activity of calcium in this process. The present work aims to shed light on the involvement of extracellular calcium in MSC differentiation: a better understanding of the early stage osteogenic differentiation program of MSC seeded on calcium-based biomaterials is required in order to develop optimal strategies to promote osteogenesis through the use of new generation osteoconductive scaffolds. A wide spectrum of analysis has been performed on time-dependent series: gene expression profiles are obtained from samples (MSC seeded on calcium-based scaffolds), together with related microRNAs expression and in vivo functional validation. On this basis, and relying on literature knowledge, hypotheses are made on the biomolecular players activated by the biomaterial calcium-phosphate component. Interestingly, a key role of miR-138 was highlighted, whose inhibition markedly increases osteogenic differentiation in vitro and enhance ectopic bone formation in vivo. Moreover, there is evidence that Ca-P substrate triggers osteogenic differentiation through genes (SMAD and RAS family) that are typically regulated during dexamethasone (DEX) induced differentiation.

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“…NGF reportedly up‐regulates the expression of adhesion molecules and stimulates the proliferation of endothelial cells (Kolostova et al, ; Raychaudhuri, Raychaudhuri, Weltman, & Farber, ) and the up‐regulated adhesion molecules attract leukocytes into the injury site during the injury repair process. Another in vitro study also demonstrated that adding NGF and BDNF to cultured bone marrow stromal cells increased the expression of the pro‐inflammatory cytokine, IL‐6 (Rezaee et al, ). In a mouse model of ear cartilage injury, pre‐treatment with NGF enhanced the healing process by directly inducing an inflammatory response and indirectly by stimulating angiogenesis (Kolostova et al, ).…”

Section: Potential Roles Of Neurotrophins In Skeletal Tissue Injury Rmentioning

confidence: 98%

Roles of neurotrophins in skeletal tissue formation and healing

Zhou

Foster

et al. 2017

Journal Cellular Physiology

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Neurotrophins and their receptors are key molecules that are known to be critical in regulating nervous system development and maintenance and have been recognized to be also involved in regulating tissue formation and healing in skeletal tissues. Studies have shown that neurotrophins and their receptors are widely expressed in skeletal tissues, implicated in chondrogenesis, osteoblastogenesis, and osteoclastogenesis, and are also involved in regulating tissue formation and healing events in skeletal tissue. Increased mRNA expression for neurotrophins NGF, BDNF, NT-3, and NT-4, and their Trk receptors has been observed in injured bone tissues, and NT-3 and its receptor, TrkC, have been identified to have the highest induction at the injury site in a drill-hole injury repair model in both bone and the growth plate. In addition, NT-3 has also recently been shown to be both an osteogenic and angiogenic factor, and this neurotrophin can also enhance expression of the key osteogenic factor, BMP-2, as well as the major angiogenic factor, VEGF, to promote bone formation, vascularization, and healing of the injury site. Further studies, however, are needed to investigate if different neurotrophins have differential roles in skeletal repair, and if NT-3 can be a potential target of intervention for promoting bone fracture healing.

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Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway.

Cited by 6 publications

References 44 publications

Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo

Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo

Osteogenic Differentiation of MSC through Calcium Signaling Activation: Transcriptomics and Functional Analysis

Roles of neurotrophins in skeletal tissue formation and healing

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