The Experts below are selected from a list of 651 Experts worldwide ranked by ideXlab platform
Dijie Li - One of the best experts on this subject based on the ideXlab platform.
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MACF1 promotes preosteoblast migration by mediating focal adhesion turnover through eb1
Biology Open, 2020Co-Authors: Peihong Su, Dijie Li, Ye Tian, Chaofei Yang, Xue Wang, Airong QianAbstract:ABSTRACT Microtubule actin crosslinking factor 1 (MACF1) is a widely expressed cytoskeletal linker and plays an essential role in various cells’ functions by mediating cytoskeleton organization and dynamics. However, the role of MACF1 on preosteoblast migration is not clear. Here, by using MACF1 knockdown and overexpressed MC3T3-E1 cells, we found MACF1 positively regulated preosteoblast migration induced by cell polarization. Furthermore, immunofluorescent staining showed that MACF1 increased end-binding protein (EB1) distribution on microtubule (MT), and decreased EB1 distribution on focal adhesion (FA) complex. Moreover, upregulation of MACF1 activated Src level and enhanced the colocalization of EB1 with activated Src. In addition, MACF1 diminished colocalization of EB1 with adenomatous polyposis coli (APC), which induced EB1 release from FA and promoted FA turnover. These results indicated an important role and mechanism of MACF1 in regulating preosteoblast migration through promoting FA turnover by mediating EB1 colocalization with Src and APC, which inferred that MACF1 might be a potential target for preventing and treating bone disorders.
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mesenchymal MACF1 facilitates smad7 nuclear translocation to drive bone formation
Cells, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract: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.
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deficiency of MACF1 in osterix expressing cells decreases bone formation by bmp2 smad runx2 pathway
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun Xiao, Zhiping Miao, Kai Dang, Xiaoyang WuAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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Deficiency of MACF1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.
Journal of Cellular and Molecular Medicine, 2019Co-Authors: Xiaoli Ma, Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun XiaoAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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MACF1 facilitates smad7 nuclear translocation to drive bone formation in mice
bioRxiv, 2019Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract:ABSTRACT MACF1 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.
Zhihao Chen - One of the best experts on this subject based on the ideXlab platform.
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mesenchymal MACF1 facilitates smad7 nuclear translocation to drive bone formation
Cells, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract: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.
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deficiency of MACF1 in osterix expressing cells decreases bone formation by bmp2 smad runx2 pathway
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun Xiao, Zhiping Miao, Kai Dang, Xiaoyang WuAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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Deficiency of MACF1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.
Journal of Cellular and Molecular Medicine, 2019Co-Authors: Xiaoli Ma, Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun XiaoAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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MACF1 facilitates smad7 nuclear translocation to drive bone formation in mice
bioRxiv, 2019Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract:ABSTRACT MACF1 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.
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microtubule actin crosslinking factor 1 MACF1 knockdown inhibits rankl induced osteoclastogenesis via akt gsk3β nfatc1 signalling pathway
Molecular and Cellular Endocrinology, 2019Co-Authors: Yunyun Xiao, Zhihao Chen, Kewen Zhang, Kai Dang, Fang Xu, Airong QianAbstract:Abstract Osteoclasts are responsible for bone resorption and play essential roles in causing bone diseases such as osteoporosis. Microtubule actin crosslinking factor 1 (MACF1) is a large spectraplakin protein that has been implicated in regulating cytoskeletal distribution, cell migration, cell survival and cell differentiation. However, whether MACF1 regulates the differentiation of osteoclasts has not been elucidated. In this study, we found that the expression of MACF1 was increased in primary bone marrow-derived monocytes (BMMs) of osteoporotic mice and was downregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis of pre-osteoclast cell lines RAW264.7 cells. RAW264.7 cells were transfected with shMACF1 using a lentiviral vector to study the role of MACF1 in osteoclastogenic differentiation. Knockdown of MACF1 in RAW264.7 cells inhibited the formation of multinucleated osteoclasts and decreased the expression of osteoclast-marker genes (Ctsk, Acp5, Mmp9 and Oscar) during RANKL-induced osteoclastogenesis. Additionally, knockdown of MACF1 disrupted actin ring formation in osteoclasts and further blocked the bone resorption activity of osteoclasts by reducing the area and depth of pits. Knockdown of MACF1 had no effect on the survival of pre-osteoclasts and mature osteoclasts. We further established that knockdown of MACF1 attenuated the phosphorylation of Akt and GSK3β and inhibited the expression of its downstream target NFATc1. Akt activator rescued the inhibition of osteoclast differentiation by MACF1 knockdown. These data demonstrate that MACF1 positively regulates osteoclast differentiation via the Akt/GSK3β/NFATc1 signalling pathway, suggesting that targeting MACF1 may be a novel therapeutic approach against osteoporosis.
Fan Zhao - One of the best experts on this subject based on the ideXlab platform.
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mesenchymal MACF1 facilitates smad7 nuclear translocation to drive bone formation
Cells, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract: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.
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deficiency of MACF1 in osterix expressing cells decreases bone formation by bmp2 smad runx2 pathway
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun Xiao, Zhiping Miao, Kai Dang, Xiaoyang WuAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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Deficiency of MACF1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.
Journal of Cellular and Molecular Medicine, 2019Co-Authors: Xiaoli Ma, Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun XiaoAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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MACF1 facilitates smad7 nuclear translocation to drive bone formation in mice
bioRxiv, 2019Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract:ABSTRACT MACF1 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.
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Mechanical unloading reduces microtubule actin crosslinking factor 1 expression to inhibit β-catenin signaling and osteoblast proliferation.
Journal of Cellular Physiology, 2018Co-Authors: Yan Zhang, Fan Zhao, Dijie Li, Zhihao Chen, Xiaoli Ma, Lifang Hu, Ye Tian, Peihong Su, Ge ZhangAbstract:: Mechanical unloading was considered a major threat to bone homeostasis, and has been shown to decrease osteoblast proliferation although the underlying mechanism is unclear. Microtubule actin crosslinking factor 1 (MACF1) is a cytoskeletal protein that regulates cellular processes and Wnt/β-catenin pathway, an essential signaling pathway for osteoblasts. However, the relationship between MACF1 expression and mechanical unloading, and the function and the associated mechanisms of MACF1 in regulating osteoblast proliferation are unclear. This study investigated effects of mechanical unloading on MACF1 expression levels in cultured MC3T3-E1 osteoblastic cells and in femurs of mice with hind limb unloading; and it also examined the role and potential action mechanisms of MACF1 in osteoblast proliferation in MACF1-knockdown, overexpressed or control MC3T3-E1 cells treated with or without the mechanical unloading condition. Results showed that the mechanical unloading condition inhibited osteoblast proliferation and MACF1 expression in MC3T3-E1 osteoblastic cells and mouse femurs. MACF1 knockdown decreased osteoblast proliferation, while MACF1 overexpression increased it. The inhibitory effect of mechanical unloading on osteoblast proliferation also changed with MACF1 expression levels. Furthermore, MACF1 was found to enhance β-catenin expression and activity, and mechanical unloading decreased β-catenin expression through MACF1. Moreover, β-catenin was found an important regulator of osteoblast proliferation, as its preservation by treatment with its agonist lithium attenuated the inhibitory effects of MACF1-knockdown or mechanical unloading on osteoblast proliferation. Taken together, mechanical unloading decreases MACF1 expression, and MACF1 up-regulates osteoblast proliferation through enhancing β-catenin signaling. This study has thus provided a mechanism for mechanical unloading-induced inhibited osteoblast proliferation.
Peihong Su - One of the best experts on this subject based on the ideXlab platform.
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MACF1 promotes preosteoblast migration by mediating focal adhesion turnover through eb1
Biology Open, 2020Co-Authors: Peihong Su, Dijie Li, Ye Tian, Chaofei Yang, Xue Wang, Airong QianAbstract:ABSTRACT Microtubule actin crosslinking factor 1 (MACF1) is a widely expressed cytoskeletal linker and plays an essential role in various cells’ functions by mediating cytoskeleton organization and dynamics. However, the role of MACF1 on preosteoblast migration is not clear. Here, by using MACF1 knockdown and overexpressed MC3T3-E1 cells, we found MACF1 positively regulated preosteoblast migration induced by cell polarization. Furthermore, immunofluorescent staining showed that MACF1 increased end-binding protein (EB1) distribution on microtubule (MT), and decreased EB1 distribution on focal adhesion (FA) complex. Moreover, upregulation of MACF1 activated Src level and enhanced the colocalization of EB1 with activated Src. In addition, MACF1 diminished colocalization of EB1 with adenomatous polyposis coli (APC), which induced EB1 release from FA and promoted FA turnover. These results indicated an important role and mechanism of MACF1 in regulating preosteoblast migration through promoting FA turnover by mediating EB1 colocalization with Src and APC, which inferred that MACF1 might be a potential target for preventing and treating bone disorders.
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mesenchymal MACF1 facilitates smad7 nuclear translocation to drive bone formation
Cells, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract: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.
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MACF1 facilitates smad7 nuclear translocation to drive bone formation in mice
bioRxiv, 2019Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Ru Zhang, Pai Wang, Yan Zhang, Peihong Su, Chaofei Yang, Lei Chen, Ye TianAbstract:ABSTRACT MACF1 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.
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Mechanical unloading reduces microtubule actin crosslinking factor 1 expression to inhibit β-catenin signaling and osteoblast proliferation.
Journal of Cellular Physiology, 2018Co-Authors: Yan Zhang, Fan Zhao, Dijie Li, Zhihao Chen, Xiaoli Ma, Lifang Hu, Ye Tian, Peihong Su, Ge ZhangAbstract:: Mechanical unloading was considered a major threat to bone homeostasis, and has been shown to decrease osteoblast proliferation although the underlying mechanism is unclear. Microtubule actin crosslinking factor 1 (MACF1) is a cytoskeletal protein that regulates cellular processes and Wnt/β-catenin pathway, an essential signaling pathway for osteoblasts. However, the relationship between MACF1 expression and mechanical unloading, and the function and the associated mechanisms of MACF1 in regulating osteoblast proliferation are unclear. This study investigated effects of mechanical unloading on MACF1 expression levels in cultured MC3T3-E1 osteoblastic cells and in femurs of mice with hind limb unloading; and it also examined the role and potential action mechanisms of MACF1 in osteoblast proliferation in MACF1-knockdown, overexpressed or control MC3T3-E1 cells treated with or without the mechanical unloading condition. Results showed that the mechanical unloading condition inhibited osteoblast proliferation and MACF1 expression in MC3T3-E1 osteoblastic cells and mouse femurs. MACF1 knockdown decreased osteoblast proliferation, while MACF1 overexpression increased it. The inhibitory effect of mechanical unloading on osteoblast proliferation also changed with MACF1 expression levels. Furthermore, MACF1 was found to enhance β-catenin expression and activity, and mechanical unloading decreased β-catenin expression through MACF1. Moreover, β-catenin was found an important regulator of osteoblast proliferation, as its preservation by treatment with its agonist lithium attenuated the inhibitory effects of MACF1-knockdown or mechanical unloading on osteoblast proliferation. Taken together, mechanical unloading decreases MACF1 expression, and MACF1 up-regulates osteoblast proliferation through enhancing β-catenin signaling. This study has thus provided a mechanism for mechanical unloading-induced inhibited osteoblast proliferation.
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MACF1 versatility in tissue specific function and in human disease
Seminars in Cell & Developmental Biology, 2017Co-Authors: Lifang Hu, Fan Zhao, Dijie Li, Zhihao Chen, Yunyun Xiao, Yan Zhang, Peihong Su, Ge Zhang, Zhipeng XiongAbstract:Abstract Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson’s disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1’s roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies.
Yunyun Xiao - One of the best experts on this subject based on the ideXlab platform.
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deficiency of MACF1 in osterix expressing cells decreases bone formation by bmp2 smad runx2 pathway
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun Xiao, Zhiping Miao, Kai Dang, Xiaoyang WuAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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Deficiency of MACF1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.
Journal of Cellular and Molecular Medicine, 2019Co-Authors: Xiaoli Ma, Fan Zhao, Dijie Li, Zhihao Chen, Kewen Zhang, Ru Zhang, Pai Wang, Yunyun XiaoAbstract:: Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of MACF1 inhibited the differentiation of MC3T3-E1 cell line. However, whether MACF1 could regulate bone formation in vivo is unclear. To study the function and mechanism of MACF1 in bone formation and osteogenic differentiation, we established osteoblast-specific Osterix (Osx) promoter-driven MACF1 conditional knockout mice (MACF1f/f Osx-Cre). The MACF1f/f Osx-Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in MACF1f/f Osx-Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in MACF1f/f Osx-Cre mice. Deficiency of MACF1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of MACF1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of MACF1f/f Osx-Cre mice. Together, these results indicated that MACF1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that MACF1 might be a therapeutic target for bone disease.
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microtubule actin crosslinking factor 1 MACF1 knockdown inhibits rankl induced osteoclastogenesis via akt gsk3β nfatc1 signalling pathway
Molecular and Cellular Endocrinology, 2019Co-Authors: Yunyun Xiao, Zhihao Chen, Kewen Zhang, Kai Dang, Fang Xu, Airong QianAbstract:Abstract Osteoclasts are responsible for bone resorption and play essential roles in causing bone diseases such as osteoporosis. Microtubule actin crosslinking factor 1 (MACF1) is a large spectraplakin protein that has been implicated in regulating cytoskeletal distribution, cell migration, cell survival and cell differentiation. However, whether MACF1 regulates the differentiation of osteoclasts has not been elucidated. In this study, we found that the expression of MACF1 was increased in primary bone marrow-derived monocytes (BMMs) of osteoporotic mice and was downregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis of pre-osteoclast cell lines RAW264.7 cells. RAW264.7 cells were transfected with shMACF1 using a lentiviral vector to study the role of MACF1 in osteoclastogenic differentiation. Knockdown of MACF1 in RAW264.7 cells inhibited the formation of multinucleated osteoclasts and decreased the expression of osteoclast-marker genes (Ctsk, Acp5, Mmp9 and Oscar) during RANKL-induced osteoclastogenesis. Additionally, knockdown of MACF1 disrupted actin ring formation in osteoclasts and further blocked the bone resorption activity of osteoclasts by reducing the area and depth of pits. Knockdown of MACF1 had no effect on the survival of pre-osteoclasts and mature osteoclasts. We further established that knockdown of MACF1 attenuated the phosphorylation of Akt and GSK3β and inhibited the expression of its downstream target NFATc1. Akt activator rescued the inhibition of osteoclast differentiation by MACF1 knockdown. These data demonstrate that MACF1 positively regulates osteoclast differentiation via the Akt/GSK3β/NFATc1 signalling pathway, suggesting that targeting MACF1 may be a novel therapeutic approach against osteoporosis.
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Microtubule actin crosslinking factor 1 (MACF1) knockdown inhibits RANKL-induced osteoclastogenesis via Akt/GSK3β/NFATc1 signalling pathway
Molecular and Cellular Endocrinology, 2019Co-Authors: Yunyun Xiao, Zhihao Chen, Kewen Zhang, Kai Dang, Fang Xu, Jianhua Ma, Airong QianAbstract:Abstract Osteoclasts are responsible for bone resorption and play essential roles in causing bone diseases such as osteoporosis. Microtubule actin crosslinking factor 1 (MACF1) is a large spectraplakin protein that has been implicated in regulating cytoskeletal distribution, cell migration, cell survival and cell differentiation. However, whether MACF1 regulates the differentiation of osteoclasts has not been elucidated. In this study, we found that the expression of MACF1 was increased in primary bone marrow-derived monocytes (BMMs) of osteoporotic mice and was downregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis of pre-osteoclast cell lines RAW264.7 cells. RAW264.7 cells were transfected with shMACF1 using a lentiviral vector to study the role of MACF1 in osteoclastogenic differentiation. Knockdown of MACF1 in RAW264.7 cells inhibited the formation of multinucleated osteoclasts and decreased the expression of osteoclast-marker genes (Ctsk, Acp5, Mmp9 and Oscar) during RANKL-induced osteoclastogenesis. Additionally, knockdown of MACF1 disrupted actin ring formation in osteoclasts and further blocked the bone resorption activity of osteoclasts by reducing the area and depth of pits. Knockdown of MACF1 had no effect on the survival of pre-osteoclasts and mature osteoclasts. We further established that knockdown of MACF1 attenuated the phosphorylation of Akt and GSK3β and inhibited the expression of its downstream target NFATc1. Akt activator rescued the inhibition of osteoclast differentiation by MACF1 knockdown. These data demonstrate that MACF1 positively regulates osteoclast differentiation via the Akt/GSK3β/NFATc1 signalling pathway, suggesting that targeting MACF1 may be a novel therapeutic approach against osteoporosis.
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MACF1 versatility in tissue specific function and in human disease
Seminars in Cell & Developmental Biology, 2017Co-Authors: Lifang Hu, Fan Zhao, Dijie Li, Zhihao Chen, Yunyun Xiao, Yan Zhang, Peihong Su, Ge Zhang, Zhipeng XiongAbstract:Abstract Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson’s disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1’s roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies.