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    Compositions and methods for bone formation and remodeling
    3.
    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：US08367822B2

    公开(公告)日：2013-02-05

    申请号：US11598916

    申请日：2006-11-14

    Applicant: Dianqing (Dan) Wu ,  Dakai Liu ,  James J. Donegan

    Inventor： Dianqing (Dan) Wu ,  Dakai Liu ,  James J. Donegan

    IPC: C07D265/34 ,  C07D498/02 ,  C07D498/12 ,  C07D265/38

    CPC classification number: A61K31/538 ,  C07D265/38 ,  C09B19/005

    Abstract: 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.

    Abstract translation: 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
    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：US20120178747A9

    公开(公告)日：2012-07-12

    申请号：US11598916

    申请日：2006-11-14

    Applicant: Dianqing (Dan) Wu ,  Dakai Liu ,  James J. Donegan

    Inventor： Dianqing (Dan) Wu ,  Dakai Liu ,  James J. Donegan

    IPC: A61K31/538 ,  C40B30/02 ,  A61K31/185 ,  A61K31/18 ,  A61K31/166 ,  C07D265/34 ,  C07D265/38 ,  C07D213/56 ,  C07C309/32 ,  C07C309/89 ,  C07C311/16 ,  C07C311/21 ,  C07C233/40 ,  A61P3/00 ,  A61P3/08 ,  A61P3/06 ,  A61P35/00 ,  A61P19/08 ,  A61P3/10 ,  A61P25/00 ,  G01N33/566

    CPC classification number: A61K31/538 ,  C07D265/38 ,  C09B19/005

    Abstract: 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.

    Abstract translation: 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 modeling
    10.
    发明授权
    Compositions and methods for bone formation and modeling 有权
    骨形成和建模的组成和方法

    公开(公告)号：US08969339B2

    公开(公告)日：2015-03-03

    申请号：US13676630

    申请日：2012-11-14

    Applicant: Enzo Biochem, Inc.

    Inventor： Dianqing (Dan) Wu ,  Dakai Liu ,  James J. Donegan

    IPC: A61K31/535 ,  C07D265/34 ,  C07D498/02 ,  C07D498/12 ,  C07D265/38 ,  A61K31/538 ,  C09B19/00

    CPC classification number: A61K31/538 ,  C07D265/38 ,  C09B19/005

    Abstract: The present disclosure is directed to methods of identifying a compound that binds to or interacts with a protein receptor involved in bone formation. Specifically, the disclosure is directed to methods of identifying a compound that regulates a Wnt pathway in a cell by binding to or interacting with cavities in proteins such as LRP5, LRP 6 and/or frizzled receptor and interfering with receptor binding to other proteins in a Wnt pathway. The present disclosure is further directed to methods and compositions that comprise an identified compound for treating or preventing a disease in a mammal in which Wnt pathway suppression plays a role.

    Abstract translation: 本公开涉及鉴定与涉及骨形成的蛋白质受体结合或与之相互作用的化合物的方法。 具体地，本公开涉及鉴定通过与蛋白质如LRP5，LRP6和/或卷曲受体中的空腔结合或与其相互作用来调节细胞中Wnt途径的化合物的方法，并干扰受体与其中的其它蛋白质的结合 Wnt途径。 本公开进一步涉及包含用于治疗或预防Wnt途径抑制起作用的哺乳动物疾病的鉴定化合物的方法和组合物。

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