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Sclerostin and the inhibition of wnt signaling and bone formation

A compound, bone injury technology, applied in the field of sclerostin and protein sclerostin, can solve problems such as bone mass increase

Inactive Publication Date: 2010-11-17
UNIV OF CONNECTICUT
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Problems solved by technology

[0006] Numerous lines of evidence suggest that enhanced LRP5 / 6-mediated canonical Wnt signaling leads to increased bone mass

Method used

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  • Sclerostin and the inhibition of wnt signaling and bone formation
  • Sclerostin and the inhibition of wnt signaling and bone formation
  • Sclerostin and the inhibition of wnt signaling and bone formation

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Embodiment Construction

[0014] Because WISE and sclerostin share homology, experiments were performed to determine whether sclerostin could have an effect on canonical Wnt signaling. The effect of conditioned medium (CM) containing mouse sclerostin on Wnt3a-induced activation of canonical Wnt signaling was determined in human embryonic kidney (HEK) cells using a LEF-1-based reporter assay. CM containing sclerostin showed significant inhibition of Wnt3a activity in a dose-dependent manner ( Figure 1A ). Higher doses were not tested as the control CM started to show significant inhibition at 50 microliters. To further confirm this effect of sclerostin, sclerostin and other canonical Wnt (Wnt1) were co-expressed in HEK cells, and sclerostin showed up to 60% inhibition of the activity of co-expressed Wnt-1 ( Figure 1B , column 2&4). Interestingly, coexpression of LRP5 abolished the antagonistic effect of sclerostin on Wnt signaling, and a slight stimulation of Wnt1 signaling by sclerostin was also ob...

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Abstract

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized byihigh 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.

Description

[0001] Related patent application reference [0002] This application is a continuation-in-part of a patent application entitled "Bone Formation and Remodeling Compositions and Methods," Application Serial No. 10 / 849,067, filed May 19, 2004. This application is also related to patent application entitled "Compositions and Methods for Stimulating or Enhancing Bone Formation and Cellular Self-Renewal," Application Serial No. 10 / 849,643, filed May 19, 2004, the contents of which are incorporated herein in their entirety as refer to. technical field [0003] The present invention relates to the protein sclerostin, which is an antagonist and / or inhibitor of Wnt proteins. When sclerostin binds to the LRP5 receptor or the LRP6 receptor (LRP5 / 6), it inhibits Wnt signaling and thus bone formation. The present invention relates to the therapeutic method, composition and application field of sclerostin in the treatment of fracture, bone disease, bone injury, bone abnormality, tumor or ...

Claims

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Application Information

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IPC IPC(8): A61K38/17C07C45/27C07D265/38A61K9/68G01N33/48G01N33/50G01N33/53G01N33/68G06F19/00
CPCG01N33/6893G01N2500/00G06F19/12G01N33/6887G16B5/00A61P19/00A61P19/08A61P19/10A61P35/00A61P43/00
Inventor D·D·吴X·李
Owner UNIV OF CONNECTICUT
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