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    Compositions and Methods for Bone Formation and Remodeling
    3.
    发明申请
    Compositions and Methods for Bone Formation and Remodeling 有权
    骨形成和重塑的组成和方法

    公开(公告)号：US20060198791A2

    公开(公告)日：2006-09-07

    申请号：US10849067

    申请日：2004-05-19

    申请人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    发明人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    IPC分类号： A61K9/68 ,  A61K7/28 ,  G01N33/53 ,  G06F19/00 ,  G01N33/48 ,  G01N33/50

    CPC分类号： G01N33/6893 ,  A61K38/00 ,  G01N33/6887 ,  G01N2500/00 ,  G01N2800/10 ,  G01N2800/108

    摘要： Abstract of the DisclosureThe mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors’ transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

    摘要翻译： 公开摘要研究了Wnt共同受体LRP5的高骨量（HBM）突变（G171V）调节规范Wnt信号传导的机制。 以前显示突变可以降低Dkk蛋白-1介导的拮抗作用，这表明G171位于第一个YWTD重复结构域可能是Dkk蛋白介导的拮抗作用的原因。 然而，我们发现第三个YWTD重复，但不是第一个重复结构域，是DKK1介导的拮抗作用所必需的。 相反，我们发现G171V突变破坏了LRP5与Mesd的相互作用，Mesd是共受体转运到细胞表面所需的LRP5 / 6的伴侣蛋白，导致细胞表面上较少的LRP5分子。 尽管细胞表面LRP5分子水平的降低导致旁分泌范例中Wnt信号传导的降低，但突变似乎不影响共表达Wnt在自分泌范式中的活性。 连同观察到成骨细胞产生自分泌的正常Wnt，Wnt7b，并且该骨细胞产生旁分泌的Dkk1，我们认为G171V突变可能通过减少旁分泌Dkk1靶向拮抗的数目而引起成骨细胞中Wnt活性的增加，而不影响 自分泌Wnt的活性。

    Compositions and methods for bone formation and remodeling
    4.
    发明授权
    Compositions and methods for bone formation and remodeling 有权
    用于骨形成和重塑的组合物和方法

    公开(公告)号：US08637506B2

    公开(公告)日：2014-01-28

    申请号：US10849067

    申请日：2004-05-19

    申请人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    发明人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    IPC分类号： A61K31/535 ,  C07C50/18

    CPC分类号： G01N33/6893 ,  A61K38/00 ,  G01N33/6887 ,  G01N2500/00 ,  G01N2800/10 ,  G01N2800/108

    摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

    摘要翻译： 研究了Wnt共同受体LRP5的高骨量（HBM）突变（G171V）调节规范Wnt信号传导的机制。 以前显示突变可以降低Dkk蛋白-1介导的拮抗作用，这表明G171位于第一个YWTD重复结构域可能是Dkk蛋白介导的拮抗作用的原因。 然而，我们发现第三个YWTD重复，但不是第一个重复结构域，是DKK1介导的拮抗作用所必需的。 相反，我们发现G171V突变破坏了LRP5与Mesd的相互作用，Mesd是共受体转运到细胞表面所需的LRP5 / 6的伴侣蛋白，导致细胞表面上较少的LRP5分子。 尽管细胞表面LRP5分子水平的降低导致旁分泌范例中Wnt信号传导的降低，但突变似乎不影响共表达Wnt在自分泌范式中的活性。 连同观察到成骨细胞产生自分泌的正常Wnt，Wnt7b，并且该骨细胞产生旁分泌的Dkk1，我们认为G171V突变可能通过减少旁分泌Dkk1靶向拮抗的目标数量引起成骨细胞中Wnt活性的增加，而不会影响 自分泌Wnt的活性。

    Compositions and methods for bone formation and remodeling
    5.
    发明申请
    Compositions and methods for bone formation and remodeling 有权
    用于骨形成和重塑的组合物和方法

    公开(公告)号：US20050196349A1

    公开(公告)日：2005-09-08

    申请号：US10849067

    申请日：2004-05-19

    申请人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    发明人： Dianqing Wu ,  Yazhou Zhang ,  Peng Liu ,  Xiaofeng Li ,  Jie Zhang ,  Jufang Shan ,  Dean Engelhardt

    IPC分类号： A61K9/68 ,  G01N33/48 ,  G01N33/50 ,  G01N33/53 ,  G01N33/68 ,  G06F19/00 ,  A61K7/28

    CPC分类号： G01N33/6893 ,  A61K38/00 ,  G01N33/6887 ,  G01N2500/00 ,  G01N2800/10 ,  G01N2800/108

    摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

    摘要翻译： 研究了Wnt共同受体LRP5的高骨量（HBM）突变（G171V）调节规范Wnt信号传导的机制。 以前显示突变可以降低Dkk蛋白-1介导的拮抗作用，这表明G171位于第一个YWTD重复结构域可能是Dkk蛋白介导的拮抗作用的原因。 然而，我们发现第三个YWTD重复，但不是第一个重复结构域，是DKK1介导的拮抗作用所必需的。 相反，我们发现G171V突变破坏了LRP5与Mesd的相互作用，Mesd是共受体转运到细胞表面所需的LRP5 / 6的伴侣蛋白，导致细胞表面上较少的LRP5分子。 尽管细胞表面LRP5分子水平的降低导致旁分泌范例中Wnt信号传导的降低，但突变似乎不影响共表达Wnt在自分泌范式中的活性。 连同观察到成骨细胞产生自分泌的正常Wnt，Wnt7b，并且该骨细胞产生旁分泌的Dkk1，我们认为G171V突变可能通过减少旁分泌Dkk1靶向拮抗的数目而引起成骨细胞中Wnt活性的增加，而不影响 自分泌Wnt的活性。

    Compositions and methods for the stimulation or enhancement of bone formation and the self-renewal of cells
    6.
    发明申请
    Compositions and methods for the stimulation or enhancement of bone formation and the self-renewal of cells 有权
    用于刺激或增强骨形成和细胞自我更新的组合物和方法

    公开(公告)号：US20050261181A1

    公开(公告)日：2005-11-24

    申请号：US10849643

    申请日：2004-05-19

    申请人： Dianqing Wu ,  Xiaofeng Li ,  Peng Liu ,  Wenzhong Liu ,  Dean Engelhardt

    发明人： Dianqing Wu ,  Xiaofeng Li ,  Peng Liu ,  Wenzhong Liu ,  Dean Engelhardt

    IPC分类号： A61K38/17

    CPC分类号： A61K38/1709

    摘要： Compositions and methods for the treatment of bone diseases, bone fractures, bone injuries and other bone abnormalities involving the use of Dkk protein, a Wnt antagonist, a Wnt inhibitor, or any other related protein for the stimulation or enhancement of mineralization and for stimulating the renewal of cells. One Dkk protein, Dickkopf-2 (Dkk-2), acts to stimulate bone formation independently of Wnt proteins which may be inhibited and/or antagonized by Dkk-2. Dkk-2 displayed enhanced specific targeting ability and enhanced biological activity in stimulating or enhancing mineralization. Dkk-2 also played a role in the differentiation and self-renewal of hematopoietic stem cells and mesenchymal stem cells, particularly in osteoblastogenesis and osteoclastogenesis.

    摘要翻译： 用于治疗骨疾病，骨折，骨损伤和涉及使用Dkk蛋白，Wnt拮抗剂，Wnt抑制剂或任何其它相关蛋白质的骨骼疾病，骨骼异常的组合物和方法，用于刺激或增强矿化和刺激 细胞更新 一种Dkk蛋白Dickkopf-2（Dkk-2）可以独立于可被Dkk-2抑制和/或拮抗的Wnt蛋白质刺激骨形成。 Dkk-2显示出增强的特异性靶向能力和增强的刺激或增强矿化的生物活性。 Dkk-2也在造血干细胞和间充质干细胞的分化和自我更新中发挥作用，特别是在成骨细胞形成和破骨细胞发生过程中。

    Compositions and methods for the stimulation or enhancement of bone formation and the self-renewal of cells
    7.
    发明授权
    Compositions and methods for the stimulation or enhancement of bone formation and the self-renewal of cells 有权
    用于刺激或增强骨形成和细胞自我更新的组合物和方法

    公开(公告)号：US08343922B2

    公开(公告)日：2013-01-01

    申请号：US10849643

    申请日：2004-05-19

    申请人： Dianqing Wu ,  Xiaofeng Li ,  Peng Liu ,  Wenzhong Liu ,  Dean Engelhardt

    发明人： Dianqing Wu ,  Xiaofeng Li ,  Peng Liu ,  Wenzhong Liu ,  Dean Engelhardt

    IPC分类号： A61K38/00 ,  A61P19/08 ,  A61P19/10

    CPC分类号： A61K38/1709

    摘要： Compositions and methods for the treatment of bone diseases, bone fractures, bone injuries and other bone abnormalities involving the use of Dkk protein, a Wnt antagonist, a Wnt inhibitor, or any other related protein for the stimulation or enhancement of mineralization and for stimulating the renewal of cells. One Dkk protein, Dickkopf-2 (Dkk-2), acts to stimulate bone formation independently of Wnt proteins which may be inhibited and/or antagonized by Dkk-2. Dkk-2 displayed enhanced specific targeting ability and enhanced biological activity in stimulating or enhancing mineralization. Dkk-2 also played a role in the differentiation and self-renewal of hematopoietic stem cells and mesenchymal stem cells, particularly in osteoblastogenesis and osteoclastogenesis.

    摘要翻译： 用于治疗骨疾病，骨折，骨损伤和涉及使用Dkk蛋白，Wnt拮抗剂，Wnt抑制剂或任何其它相关蛋白质的骨骼疾病，骨骼异常的组合物和方法，用于刺激或增强矿化和刺激 细胞更新 一种Dkk蛋白Dickkopf-2（Dkk-2）可以独立于可被Dkk-2抑制和/或拮抗的Wnt蛋白质刺激骨形成。 Dkk-2显示出增强的特异性靶向能力和增强的刺激或增强矿化的生物活性。 Dkk-2也在造血干细胞和间充质干细胞的分化和自我更新中发挥作用，特别是在成骨细胞形成和破骨细胞发生过程中。

    Sclerostin and the inhibition of WNT signaling and bone formation
    8.
    发明申请
    Sclerostin and the inhibition of WNT signaling and bone formation 有权
    硬皮蛋白和抑制WNT信号和骨形成

    公开(公告)号：US20120115787A9

    公开(公告)日：2012-05-10

    申请号：US11084668

    申请日：2005-03-18

    申请人： Dianqing Wu ,  Xiaofeng Li

    发明人： Dianqing Wu ,  Xiaofeng Li

    IPC分类号： A61K38/17

    CPC分类号： G01N33/6893 ,  G01N33/6887 ,  G01N2500/00 ,  G06F19/12

    摘要： The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass (HBM). In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.

    摘要翻译： SOST基因产物硬化蛋白的丧失导致以高骨量（HBM）为特征的硬皮病。 在本报告中，我们发现硬皮蛋白可以拮抗人类胚胎肾A293细胞和小鼠成骨细胞MC3T3细胞中的典型Wnt信号。 这种硬脂蛋白介导的拮抗作用可以通过Wnt共同受体LRP5的过度表达来逆转。 此外，我们发现硬骨素与LRP5以及LRP6结合，并鉴定出LRP5的前两个YWTD-EGF重复结构域负责结合。 虽然这两个重复结构域是转导规范Wnt信号所必需的，但是典型的Wnt似乎没有与硬皮蛋白竞争结合LRP5。 在原发性颅骨成骨细胞分化过程中，考察了sclerostin和Wnt7b（一种自分泌标准Wnt）的表达，表明硬骨素在成骨细胞分化后期表达，与成骨标志物骨钙素表达相符，Wnt7b表达后表达。 鉴于许多证据表明典型的Wnt信号传导刺激成骨，我们认为与硬化蛋白的丧失有关的HBM表型可能至少部分归因于由于硬骨素介导的Wnt拮抗作用降低导致的典型Wnt信号传导的增加。

    Sclerostin and the inhibition of WNT signaling and bone formation
    9.
    发明申请
    Sclerostin and the inhibition of WNT signaling and bone formation 有权

    公开(公告)号：US20060030523A1

    公开(公告)日：2006-02-09

    申请号：US11084668

    申请日：2005-03-18

    申请人： Dianqing Wu ,  Xiaofeng Li

    发明人： Dianqing Wu ,  Xiaofeng Li

    IPC分类号： A61K38/17

    CPC分类号： G01N33/6893 ,  G01N33/6887 ,  G01N2500/00 ,  G06F19/12

    摘要： The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass (HBM). In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.