The Experts below are selected from a list of 1926 Experts worldwide ranked by ideXlab platform

Yingjie Guan - One of the best experts on this subject based on the ideXlab platform.

  • mechanical and il 1β responsive mir 365 contributes to osteoarthritis development by targeting Histone Deacetylase 4
    International Journal of Molecular Sciences, 2016
    Co-Authors: Xu Yang, Yingjie Guan, Shaoqi Tian, Yuanhe Wang, Qian Chen
    Abstract:

    Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed Histone Deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.

  • microrna 1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development
    The FASEB Journal, 2014
    Co-Authors: Pengcui Li, Yingjie Guan, Qian Chen, Tingcun Zhao
    Abstract:

    MicroRNAs (miRs) are noncoding RNAs (17–25 nt) that control translation and/or mRNA degradation. Using Northern blot analysis, we identified that miR-1 is specifically expressed in growth plate cartilage in addition to muscle tissue, but not in brain, intestine, liver, or lung. We obtained the first evidence that miR-1 is highly expressed in the hypertrophic zone of the growth plate, with an 8-fold increase compared with the proliferation zone; this location coincides with the Ihh and Col X expression regions in vivo. MiR-1 significantly induces chondrocyte proliferation and differentiation. We further identified Histone Deacetylase 4 (HDAC4) as a target of miR-1. HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. MiR-1 inhibits both endogenous HDAC4 protein by 2.2-fold and the activity of a reporter gene bearing the 3′-untranslated region (UTR) of HDAC4 by 3.3-fold. Conversely, knockdown of endogenous miR-1 relieves the repression of HDAC4. Deletion of the miR-1 binding site in HDAC4 3′-UTR or mutated miR-1 abolishes miR-1-mediated inhibition of the reporter gene activity. Overexpression of HDAC4 reverses miR-1 induction of chondrocyte differentiation markers Col X and Ihh. HDAC4 inhibits Runx2 promoter activity in a dosage-dependent manner. Thus, miR-1 plays an important role in the regulation of the chondrocyte phenotype during the growth plate development via direct targeting of HDAC4. — Li, P., Wei, X., Guan, Y., Chen, Q., Zhao, T., Sun, C., Wei, L. MicroRNA-1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development.

  • subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through ca2 calmodulin dependent kinase iv
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular Relocation of Histone Deacetylase 4 Regulates Growth Plate
    2012
    Co-Authors: Yingjie Guan, Paul Haines, Ming Pei, Richard M. Terek, Xiaochun Wei, Tingcun Zhao, Qian Chen, Xu Yang, Lei Wei
    Abstract:

    Tingcun Zhao, Lei Wei 1, * 5 6 Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 7 402A, 1 Hoppin Street, Providence RI 02903. Department of Orthopaedics, West Virginia University, 8 Morgantown, WV 26506. Department of Orthopaedics, The Second Hospital of Shanxi Medical 9 University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China. Department 10 of Surgery, Warren Alpert Medical School of Brown University, Providence RI 02903. 11 12 13 Running title: HDAC4 regulates growth plate development 14 15 *Address reprint requests to: Lei_Wei@brown.edu 16 17 18 Articles in PresS. Am J Physiol Cell Physiol (March 21, 2012). doi:10.1152/ajpcell.00348.2011

Qian Chen - One of the best experts on this subject based on the ideXlab platform.

  • mechanical and il 1β responsive mir 365 contributes to osteoarthritis development by targeting Histone Deacetylase 4
    International Journal of Molecular Sciences, 2016
    Co-Authors: Xu Yang, Yingjie Guan, Shaoqi Tian, Yuanhe Wang, Qian Chen
    Abstract:

    Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed Histone Deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.

  • microrna 1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development
    The FASEB Journal, 2014
    Co-Authors: Pengcui Li, Yingjie Guan, Qian Chen, Tingcun Zhao
    Abstract:

    MicroRNAs (miRs) are noncoding RNAs (17–25 nt) that control translation and/or mRNA degradation. Using Northern blot analysis, we identified that miR-1 is specifically expressed in growth plate cartilage in addition to muscle tissue, but not in brain, intestine, liver, or lung. We obtained the first evidence that miR-1 is highly expressed in the hypertrophic zone of the growth plate, with an 8-fold increase compared with the proliferation zone; this location coincides with the Ihh and Col X expression regions in vivo. MiR-1 significantly induces chondrocyte proliferation and differentiation. We further identified Histone Deacetylase 4 (HDAC4) as a target of miR-1. HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. MiR-1 inhibits both endogenous HDAC4 protein by 2.2-fold and the activity of a reporter gene bearing the 3′-untranslated region (UTR) of HDAC4 by 3.3-fold. Conversely, knockdown of endogenous miR-1 relieves the repression of HDAC4. Deletion of the miR-1 binding site in HDAC4 3′-UTR or mutated miR-1 abolishes miR-1-mediated inhibition of the reporter gene activity. Overexpression of HDAC4 reverses miR-1 induction of chondrocyte differentiation markers Col X and Ihh. HDAC4 inhibits Runx2 promoter activity in a dosage-dependent manner. Thus, miR-1 plays an important role in the regulation of the chondrocyte phenotype during the growth plate development via direct targeting of HDAC4. — Li, P., Wei, X., Guan, Y., Chen, Q., Zhao, T., Sun, C., Wei, L. MicroRNA-1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development.

  • subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through ca2 calmodulin dependent kinase iv
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular Relocation of Histone Deacetylase 4 Regulates Growth Plate
    2012
    Co-Authors: Yingjie Guan, Paul Haines, Ming Pei, Richard M. Terek, Xiaochun Wei, Tingcun Zhao, Qian Chen, Xu Yang, Lei Wei
    Abstract:

    Tingcun Zhao, Lei Wei 1, * 5 6 Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 7 402A, 1 Hoppin Street, Providence RI 02903. Department of Orthopaedics, West Virginia University, 8 Morgantown, WV 26506. Department of Orthopaedics, The Second Hospital of Shanxi Medical 9 University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China. Department 10 of Surgery, Warren Alpert Medical School of Brown University, Providence RI 02903. 11 12 13 Running title: HDAC4 regulates growth plate development 14 15 *Address reprint requests to: Lei_Wei@brown.edu 16 17 18 Articles in PresS. Am J Physiol Cell Physiol (March 21, 2012). doi:10.1152/ajpcell.00348.2011

Tingcun Zhao - One of the best experts on this subject based on the ideXlab platform.

  • microrna 1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development
    The FASEB Journal, 2014
    Co-Authors: Pengcui Li, Yingjie Guan, Qian Chen, Tingcun Zhao
    Abstract:

    MicroRNAs (miRs) are noncoding RNAs (17–25 nt) that control translation and/or mRNA degradation. Using Northern blot analysis, we identified that miR-1 is specifically expressed in growth plate cartilage in addition to muscle tissue, but not in brain, intestine, liver, or lung. We obtained the first evidence that miR-1 is highly expressed in the hypertrophic zone of the growth plate, with an 8-fold increase compared with the proliferation zone; this location coincides with the Ihh and Col X expression regions in vivo. MiR-1 significantly induces chondrocyte proliferation and differentiation. We further identified Histone Deacetylase 4 (HDAC4) as a target of miR-1. HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. MiR-1 inhibits both endogenous HDAC4 protein by 2.2-fold and the activity of a reporter gene bearing the 3′-untranslated region (UTR) of HDAC4 by 3.3-fold. Conversely, knockdown of endogenous miR-1 relieves the repression of HDAC4. Deletion of the miR-1 binding site in HDAC4 3′-UTR or mutated miR-1 abolishes miR-1-mediated inhibition of the reporter gene activity. Overexpression of HDAC4 reverses miR-1 induction of chondrocyte differentiation markers Col X and Ihh. HDAC4 inhibits Runx2 promoter activity in a dosage-dependent manner. Thus, miR-1 plays an important role in the regulation of the chondrocyte phenotype during the growth plate development via direct targeting of HDAC4. — Li, P., Wei, X., Guan, Y., Chen, Q., Zhao, T., Sun, C., Wei, L. MicroRNA-1 regulates chondrocyte phenotype by repressing Histone Deacetylase 4 during growth plate development.

  • subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through ca2 calmodulin dependent kinase iv
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular Relocation of Histone Deacetylase 4 Regulates Growth Plate
    2012
    Co-Authors: Yingjie Guan, Paul Haines, Ming Pei, Richard M. Terek, Xiaochun Wei, Tingcun Zhao, Qian Chen, Xu Yang, Lei Wei
    Abstract:

    Tingcun Zhao, Lei Wei 1, * 5 6 Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 7 402A, 1 Hoppin Street, Providence RI 02903. Department of Orthopaedics, West Virginia University, 8 Morgantown, WV 26506. Department of Orthopaedics, The Second Hospital of Shanxi Medical 9 University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China. Department 10 of Surgery, Warren Alpert Medical School of Brown University, Providence RI 02903. 11 12 13 Running title: HDAC4 regulates growth plate development 14 15 *Address reprint requests to: Lei_Wei@brown.edu 16 17 18 Articles in PresS. Am J Physiol Cell Physiol (March 21, 2012). doi:10.1152/ajpcell.00348.2011

Xu Yang - One of the best experts on this subject based on the ideXlab platform.

  • mechanical and il 1β responsive mir 365 contributes to osteoarthritis development by targeting Histone Deacetylase 4
    International Journal of Molecular Sciences, 2016
    Co-Authors: Xu Yang, Yingjie Guan, Shaoqi Tian, Yuanhe Wang, Qian Chen
    Abstract:

    Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed Histone Deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.

  • subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through ca2 calmodulin dependent kinase iv
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular relocation of Histone Deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Yingjie Guan, Paul Haines, Richard M. Terek, Qian Chen, Xu Yang, Tingcun Zhao
    Abstract:

    Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that Histone Deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

  • Subcellular Relocation of Histone Deacetylase 4 Regulates Growth Plate
    2012
    Co-Authors: Yingjie Guan, Paul Haines, Ming Pei, Richard M. Terek, Xiaochun Wei, Tingcun Zhao, Qian Chen, Xu Yang, Lei Wei
    Abstract:

    Tingcun Zhao, Lei Wei 1, * 5 6 Department of Orthopaedics, Warren Alpert Medical School of Brown University, CORO West, Suite 7 402A, 1 Hoppin Street, Providence RI 02903. Department of Orthopaedics, West Virginia University, 8 Morgantown, WV 26506. Department of Orthopaedics, The Second Hospital of Shanxi Medical 9 University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China. Department 10 of Surgery, Warren Alpert Medical School of Brown University, Providence RI 02903. 11 12 13 Running title: HDAC4 regulates growth plate development 14 15 *Address reprint requests to: Lei_Wei@brown.edu 16 17 18 Articles in PresS. Am J Physiol Cell Physiol (March 21, 2012). doi:10.1152/ajpcell.00348.2011

  • mir 365 a mechanosensitive microrna stimulates chondrocyte differentiation through targeting Histone Deacetylase 4
    The FASEB Journal, 2011
    Co-Authors: Yingjie Guan, Xu Yang, Qian Chen
    Abstract:

    Mechanical stress plays an essential role in tissue development and remodeling. In this study, we determined the role of microRNA in chondrocyte mechanotransduction. Using microarray, we identified miR-365 as a mechanoresponsive microRNA in parallel to mechanical induction of Indian hedgehog (Ihh) in primary chicken chondrocytes cultured in 3-dimensional collagen scaffoldings under cyclic loading (1 Hz, 5% elongation). Interestingly, expression of miR-365 is elevated in the prehypertrophic zone of the growth plate, coinciding with the Ihh expression region in vivo. MiR-365 significantly stimulates chondrocyte proliferation and differentiation. MiR-365 increases expression of Ihh and the hypertrophic marker type X collagen, whereas anti-miR-365 inhibits the expression of these genes. We identified Histone Deacetylase 4 (HDAC4), an inhibitor of chondrocyte hypertrophy, as a target of miR-365. MiR-365 inhibits both endogenous HDAC4 protein levels as well as the activity of a reporter gene bearing the 3′-untr...

Fang Wang - One of the best experts on this subject based on the ideXlab platform.

  • regulation of tamoxifen resistance in estrogen receptor positive mcf 7 breast cancer cells by microrna 10b targeting Histone Deacetylase 4
    Chinese journal of experimental surgery, 2018
    Co-Authors: Jianxiang Zhang, Fang Wang
    Abstract:

    Objective To investigate the effect of microRNA-10b (miR-10b) targeting Histone Deacetylase 4 (HDAC4) on the resistance of estrogen receptor positive (ER+ ) MCF-7 breast cancer cells to tamoxifen. Methods ER+ and tamoxifen resistant MCF-7 cell line MCF-7-TR was established, and miR-10b expression level in MCF-7 cells and MCF-7-TR cells was detected by reverse transcription real-time quantitative polymerase chain reaction (Real-time PCR). Methyl thiazol tetrazolium (MTT) and trypan blue were used to detect the proliferation and activity of MCF-7 cells and MCF-7-TR cells transfected with pre-miR-10b, miR-10b inhibitor and siHDAC4 at different tamoxifen concentrations (0, 5, 10, 15, 20, 30 μmol/L), respectively. The expression of HDAC4 protein was detected by Western blotting. Results Taken expression level and invasive ability of miR-10b in MCF-7 breast cancer cells as the standard, the miR-10b expression level and invasion ability of MCF-7-TR cell breast cancer cells were 7.2±1.1 and 5.3±1.3 respectively. With the increase of the concentration of tamoxifen, decreased the rate of cell proliferation in MCF-7 cells, which is most obvious, followed by MCF-7-TR+ miR-10b inhibitor + siHDAC4 and MCF-7+ pre-miR-10b+ HDAC4 cells, and the proliferation of MCF-7-TR+ siHDAC4 cells and MCF-7-TR cells decreased the rate of the lowest. The migration ability of MCF-7 cells and MCF-7-TR+ miR-10b cells of the inhibitor decreased most, MCF-7+ pre-miR-10b+ and tamoxifen (10 μmol/L) MCF-7-TR+ cells and tamoxifen (10 μmol/L) had no significant difference in the ability of cell migration (t=1.116, P=0.272), but was significantly higher than that of MCF-7 cells and MCF-7-TR+ miR-10b cells (t=0.124, 10.769, 14.569, 11.577, P=0.000). The expression level of HDAC4 protein in MCF-7+ pre-miR-10b cells was lower than that in MCF-7 cells, MCF-7-TR cells, HDAC4 protein expression level, MCF-7-TR+ miR-10b inhibitor cells, MCF-7+ siHDAC4 cells HDAC4 protein expression level was lower than MCF-7 cells. Conclusion The miR-10b-HDAC4 signaling pathway may be a molecular mechanism of tamoxifen resistance in breast cancer. Key words: Breast cancer; Estrogen receptor positive; Tamoxifen resistance; MicroRNA-10b; Histone Deacetylase 4

  • The Histone Deacetylase 4/SP1/microrna‐200a regulatory network contributes to aberrant Histone acetylation in hepatocellular carcinoma
    Hepatology, 2011
    Co-Authors: Jihang Yuan, Fu Yang, Bifeng Chen, Zhi Lu, Weiping Zhou, Fang Wang
    Abstract:

    As an important epigenetic mechanism, Histone acetylation modulates the transcription of many genes and plays important roles in hepatocellular carcinoma (HCC). Aberrations in Histone acetylation have been observed in HCC, but the factors that contribute to the aberrations have not been fully elucidated. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in important epigenetic mechanisms. In this study, we determined that miR-200a and the level of Histone H3 acetylation at its promoter were reduced in human HCC tissues in comparison with adjacent noncancerous hepatic tissues. Furthermore, our results suggested that the Histone Deacetylase 4 (HDAC4) inhibited the expression of miR-200a and its promoter activity and reduced the Histone H3 acetylation level at the mir-200a promoter through a Sp1-dependent pathway. Interestingly, we observed that the miR-200a directly targeted the 3′-untranslated region of the HDAC4 messenger RNA and repressed expression of HDAC4. Therefore, miR-200a ultimately induced its own transcription and increased the Histone H3 acetylation level at its own promoter. Through targeting HDAC4, miR-200a also induced the up-regulation of total acetyl-Histone H3 levels and increased the Histone H3 acetylation level at the p21WAF/Cip1 promoter. Finally, we determined that miR-200a inhibited the proliferation and migration of HCC cells in vivo and in vitro. Conclusion: Our findings suggest that the HDAC4/Sp1/miR-200a regulatory network induces the down-regulation of miR-200a and the up-regulation of HDAC4 in HCC. As a result, down-regulation of miR-200a enhances the proliferation and migration of HCC cells and induces aberrant Histone acetylation in HCC. These findings highlight a potential therapeutic approach in targeting the HDAC4/Sp1/miR-200a regulatory network for the treatment of HCC. (HEPATOLOGY 2011

  • the Histone Deacetylase 4 sp1 microrna 200a regulatory network contributes to aberrant Histone acetylation in hepatocellular carcinoma
    Hepatology, 2011
    Co-Authors: Jihang Yuan, Fu Yang, Bifeng Chen, Zhi Lu, Weiping Zhou, Fang Wang
    Abstract:

    As an important epigenetic mechanism, Histone acetylation modulates the transcription of many genes and plays important roles in hepatocellular carcinoma (HCC). Aberrations in Histone acetylation have been observed in HCC, but the factors that contribute to the aberrations have not been fully elucidated. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in important epigenetic mechanisms. In this study, we determined that miR-200a and the level of Histone H3 acetylation at its promoter were reduced in human HCC tissues in comparison with adjacent noncancerous hepatic tissues. Furthermore, our results suggested that the Histone Deacetylase 4 (HDAC4) inhibited the expression of miR-200a and its promoter activity and reduced the Histone H3 acetylation level at the mir-200a promoter through a Sp1-dependent pathway. Interestingly, we observed that the miR-200a directly targeted the 3′-untranslated region of the HDAC4 messenger RNA and repressed expression of HDAC4. Therefore, miR-200a ultimately induced its own transcription and increased the Histone H3 acetylation level at its own promoter. Through targeting HDAC4, miR-200a also induced the up-regulation of total acetyl-Histone H3 levels and increased the Histone H3 acetylation level at the p21WAF/Cip1 promoter. Finally, we determined that miR-200a inhibited the proliferation and migration of HCC cells in vivo and in vitro. Conclusion: Our findings suggest that the HDAC4/Sp1/miR-200a regulatory network induces the down-regulation of miR-200a and the up-regulation of HDAC4 in HCC. As a result, down-regulation of miR-200a enhances the proliferation and migration of HCC cells and induces aberrant Histone acetylation in HCC. These findings highlight a potential therapeutic approach in targeting the HDAC4/Sp1/miR-200a regulatory network for the treatment of HCC. (HEPATOLOGY 2011