scholarly journals MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation in Mice

2019 ◽  
Author(s):  
Fan Zhao ◽  
Xiaoli Ma ◽  
Wuxia Qiu ◽  
Pai Wang ◽  
Ru Zhang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Developmental Stages ◽  
Nuclear Translocation ◽  
Bone Diseases ◽  
Neuron Development ◽  
Cellular Functions ◽  
Conditional Gene Targeting ◽  
Deficient Mice ◽  
Cytoskeleton Integrity

ABSTRACTMACF1 is a large crosslinker that contributes to cytoskeleton integrity and cell differentiation. Loss of MACF1 impairs multiple cellular functions in neuron development and epidermal migration, and is the molecular basis for many diseases such as heart failure and Parkinson’s disease. MACF1 is highly abundant in bones, however, its involvements in osteogenic differentiation and bone formation are still unknown. In this study, by conditional gene targeting to delete the Macf1 gene specifically in MSCs, we observed ossification retardation and bone loss in MACF1 deficient mice in different developmental stages, which we traced to disorganized cytoskeleton and decreased osteogenic differentiation capability in MSCs. Further, we show that MACF1 interacts and facilitates SMAD7 nuclear translocation to initiate downstream transcription. These findings are hopefully to expand the biological scope of MACF1 in bones, and provide experimental basis for targeting MACF1 in degenerative bone diseases such as osteoporosis.

scholarly journals Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

2020 ◽  
Author(s):  
Amitabh Das ◽  
Xiaobei Wang ◽  
Jessica Kang ◽  
Alyssa Coulter ◽  
Amol C. Shetty ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Nuclear Translocation ◽  
De Novo ◽  
Primary Source ◽  
Regulatory Elements ◽  
Monocyte Subsets ◽  
Enhancer Activity ◽  
Signaling Receptors ◽  
Early Developmental ◽  
Deficient Mice

SUMMARYOsteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C− monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8 deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation.

scholarly journals TNF-α-induced NF-κB activation upregulates microRNA-150-3p and inhibits osteogenesis of mesenchymal stem cells by targeting β-catenin

Open Biology ◽  
2016 ◽  
Vol 6 (3) ◽  
pp. 150258 ◽  
Author(s):  
Nan Wang ◽  
Zubin Zhou ◽  
Tianyi Wu ◽  
Wei Liu ◽  
Peipei Yin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Bone Cells ◽  
Bone Diseases ◽  
Cytokine Activation ◽  
Tnf Α ◽  
Marrow Mesenchymal Stem Cells ◽  
Underlying Mechanisms

Although systemic or local inflammation, commonly featured by cytokine activation, is implicated in patients with bone loss, the underlying mechanisms are still elusive. As microRNAs (miR), a class of small non-coding RNAs involved in essential physiological processes, have been found in bone cells, we aimed to investigate the role of miR for modulating osteogenesis in inflammatory milieu using human bone marrow mesenchymal stem cells (hBM-MSCs). Induced by proinflammatory cytokine TNF-α, miR-150-3p was identified as a key player in suppressing osteogenic differentiation through downregulating β-catenin, a transcriptional co-activator promoting bone formation. TNF-α treatment increased the levels of miR-150-3p, which directly targeted the 3′-UTR of β-catenin mRNA and in turn repressed its expression. In addition, we observed that miR-150-3p expression was increased by TNF-α via IKK-dependent NF-κB signalling. There are three putative NF-κB binding sites in the promoter region of miR-150, and we identified −686 region as the major NF-κB binding site for stimulation of miR-150 expression by TNF-α. Finally, the osteogenic differentiation of hBM-MSCs was inhibited by either miR-150-3p overexpression or TNF-α treatment, which was prevented by anti-miR-150-3p oligonucleotides. Taken together, our data suggested that miR-150-3p integrated inflammation signalling and osteogenic differentiation and may contribute to the inhibition effects of inflammation on bone formation, thus expanding the pathophysiological functions of microRNAs in bone diseases.

scholarly journals Mesenchymal MACF1 Facilitates SMAD7 Nuclear Translocation to Drive Bone Formation

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 616 ◽  
Author(s):  
Fan Zhao ◽  
Xiaoli Ma ◽  
Wuxia Qiu ◽  
Pai Wang ◽  
Ru Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Formation ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Bone Microarchitecture ◽  
Bone Diseases ◽  
Conditional Knockout ◽  
Osteoporotic Bone ◽  
Cell Integrity

Microtubule actin crosslinking factor 1 (MACF1) is a large crosslinker that contributes to cell integrity and cell differentiation. Recent studies show that MACF1 is involved in multiple cellular functions such as neuron development and epidermal migration, and is the molecular basis for many degenerative diseases. MACF1 is highly abundant in bones, especially in mesenchymal stem cells; however, its regulatory role is still less understood in bone formation and degenerative bone diseases. In this study, we found MACF1 expression in mesenchymal stem cells (MSCs) of osteoporotic bone specimens was significantly lower. By conditional gene targeting to delete the mesenchymal Macf1 gene in mice, we observed in MSCs decreased osteogenic differentiation capability. During early stage bone development, the MACF1 conditional knockout (cKO) mice exhibit significant ossification retardation in skull and hindlimb, and by adulthood, mesenchymal loss of MACF1 attenuated bone mass, bone microarchitecture, and bone formation capability significantly. Further, we showed that MACF1 interacts directly with SMAD family member 7 (SMAD7) and facilitates SMAD7 nuclear translocation to initiate downstream osteogenic pathways. Hopefully these findings will expand the biological scope of the MACF1 gene, and provide an experimental basis for targeting MACF1 in degenerative bone diseases such as osteoporosis.

scholarly journals Silencing of lncRNA AK045490 Promotes Osteoblast Differentiation and Bone Formation via β-Catenin/TCF1/Runx2 Signaling Axis

2019 ◽  
Vol 20 (24) ◽  
pp. 6229 ◽  
Author(s):  
Dijie Li ◽  
Ye Tian ◽  
Chong Yin ◽  
Ying Huai ◽  
Yipu Zhao ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Noncoding Rna ◽  
Osteoblast Differentiation ◽  
Nuclear Translocation ◽  
Mice Model ◽  
Structural Deterioration ◽  
Age Related

Osteoporosis, a disease characterized by both loss of bone mass and structural deterioration of bone, is the most common reason for a broken bone among the elderly. It is known that the attenuated differentiation ability of osteogenic cells has been regarded as one of the greatest contributors to age-related bone formation reduction. However, the effects of current therapies are still unsatisfactory. In this study we identify a novel long noncoding RNA AK045490 which is correlated with osteogenic differentiation and enriched in skeletal tissues of mice. In vitro analysis of bone-derived mesenchymal stem cells (BMSCs) showed that AK045490 inhibited osteoblast differentiation. In vivo inhibition of AK045490 by its small interfering RNA rescued bone formation in ovariectomized osteoporosis mice model. Mechanistically, AK045490 inhibited the nuclear translocation of β-catenin and downregulated the expression of TCF1, LEF1, and Runx2. The results suggest that Lnc-AK045490 suppresses β-catenin/TCF1/Runx2 signaling and inhibits osteoblast differentiation and bone formation, providing a novel mechanism of osteogenic differentiation and a potential drug target for osteoporosis.

scholarly journals MicroRNA-378 suppressed osteogenesis of mesenchymal stem cells and impaired bone formation via inactivating Wnt/β-catenin signaling

2019 ◽  
Author(s):  
Lu Feng ◽  
Jin-fang Zhang ◽  
Liu Shi ◽  
Zheng-meng Yang ◽  
Tian-yi Wu ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Bone Development ◽  
Healing Process ◽  
Underlying Mechanism ◽  
Bone Diseases ◽  
Transcriptional Level ◽  
Human Mscs ◽  
Bona Fide

AbstractMicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional level. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MiR-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of MSCs derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed while anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members Wnt6 and Wnt10a were identified as bona fide targets of miR-378, and their expression were decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the sh-miR-378 modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate healing process in vivo. In conclude, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting miR-378 may be a potential therapeutic target for bone diseases.

Reduced bone formation and increased adiposity with insulin resistance in interleukin-11 deficient mice

2014 ◽  
Author(s):  
Bingzi Dong ◽  
Takeshi Kondo ◽  
Yukiyo Ohnishi ◽  
Itsuro Endo ◽  
Masahiro Abe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Formation ◽  
Interleukin 11 ◽  
Deficient Mice

MiR-144-3p Inhibits BMSC Proliferation and Osteogenic Differentiation Via Targeting FZD4 in Steroid-Associated Osteonecrosis

2020 ◽  
Vol 25 (45) ◽  
pp. 4806-4812 ◽  
Author(s):  
Zhibo Sun ◽  
Fei Wu ◽  
Yue Yang ◽  
Feng Liu ◽  
Fengbo Mo ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Nuclear Translocation ◽  
Bone Diseases ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Alizarin Red ◽  
Over Expression ◽  
Negative Effect ◽  
Proliferation Ability

Background: MicroRNAs have recently been recognized to be engaged in the development of bone diseases. Objective: This study was performed to elucidate the effects of miR-144-3p on proliferation and osteogenesis of mesenchymal stem cells (MSCs) from the patients with steroid-associated osteonecrosis (ONFH) and its related mechanism. Method: The expression level of miR-144-3p in the MSCs from the proximal femur of the patients was examined by Real-time PCR. The cell proliferation ability was assayed by MTT. The differentiation ability of MSCs was assayed by Alizarin Red S (ARS) staining. The interaction between miR-144-3p and frizzled4 (FZD4) was investigated by Real-time PCR, western blot and luciferase reporter assay. Results: ONFH samples had the obviously high expression of miR-144-3p compared to the control. MiR-144-3p had a negative effect on the proliferation and osteogenesis of MSCs. Via targeting FZD4, miR-144-3p decreased β-catenin nuclear translocation, the transcription of RUNX2 and COL1A1. Over-expression of FZD4 partially reversed miR-144-3p-induced decrease in the proliferation and osteogenesis of MSCs. Conclusion: MiR-144-3p might play an important role in the development of ONFH and might be used as a novel class of therapeutic targets for this disease.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Ions release behavior of vanadium-doped mesoporous bioactive glass particles and effect on BMSCs osteogenic differentiation via FAK/MAPK signaling pathway

2021 ◽  
Author(s):  
Jiangfeng Li ◽  
Junying Li ◽  
Yuhao Wei ◽  
Na Xu ◽  
Jingtao Li ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bioactive Glass ◽  
Osteogenic Differentiation ◽  
Bone Growth ◽  
Mapk Signaling ◽  
Release Behavior ◽  
Pentavalent Vanadium ◽  
Important Trace Element ◽  
Vanadium Ions ◽  
Mesoporous Bioactive Glass

Vanadium is an important trace element in bone to involve in bone metabolism, bone formation, and bone growth, but roles of various vanadium ions, especially pentavalent vanadium, in bone tissue...

scholarly journals Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Chao Liu ◽  
An-Song Liu ◽  
Da Zhong ◽  
Cheng-Gong Wang ◽  
Mi Yu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulatory System ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Integrin Αv

AbstractBone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

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