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Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis
Thesis (PhD)--University of Pretoria, 2020.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2021
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| _version_ | 1867613531737686016 |
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| access_status_str | Open Access |
| author2 | Naidoo, Vinny |
| author_browse | Naidoo, Vinny |
| author_facet | Naidoo, Vinny |
| collection | Thesis |
| dc_rights_str_mv | © 2021 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD)--University of Pretoria, 2020. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/82607 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:38.105Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/82607 Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis Naidoo, Vinny u15413706@tuks.co.za McGaw, Lyndy Joy Dreyer, Timothy James UCTD sclerostin bone formation sclerosteosis Veterinary science theses SDG-02 Veterinary science theses SDG-03 Veterinary science theses SDG-12 Thesis (PhD)--University of Pretoria, 2020. Sclerosteosis is a severe autosomal recessive sclerosing skeletal dysplasia with no available treatment. It is characterised by excessive bone formation and is caused by mutations in the SOST gene that lead to loss of expression of sclerostin, a protein that acts as a negative regulator of bone formation by binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) Wnt co-receptors to inhibit the canonical Wnt/β-catenin signalling pathway. This study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis. Recombinant wild type mouse sclerostin (mScl) and two novel mScl fusion proteins containing a C-terminal human immunoglobulin G1 (IgG1) antibody fraction crystallisable (mScl hFc), or C-terminal human Fc with a poly-aspartate motif (mScl hFc PD), to increase serum half-life and promote localisation to bone, respectively, were produced and purified using mammalian expression and standard chromatography techniques. These recombinant mScl proteins bound to LRP6 with high affinity (nM range) and completely inhibited matrix mineralisation in an in vitro bone nodule formation assay. Pharmacokinetic assessment following a single dose administered to wild type (WT) or SOST knock out (SOST-/-) mice indicated that the presence of the hFc increased protein half-life from less than 5 minutes to at least 1.5 days. The effect of a 6-week treatment with these proteins on the skeletal phenotype of young SOST-/- mice revealed that mScl hFc PD treatment resulted in a modest but significant reduction in trabecular bone volume compared with the vehicle control. There was no marked effect on cortical bone indices assessed by μCT, whole body areal bone mineral density by DXA, or terminal levels of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) in any of the SOST-/- or WT treatment groups, possibly due to insufficient exposure. Administration of recombinant mScl hFc PD protein partially corrected the high bone mass phenotype of the SOST-/- mouse, suggesting that bone-targeting of sclerostin engineered to improve half-life was able to negatively regulate bone formation in the SOST-/- mouse model of sclerosteosis. However, the modest efficacy indicates that sclerostin replacement may not be an optimal strategy to mitigate excessive bone formation in sclerosteosis, hence alternative approaches should be explored. UCB Pharma (Slough, UK) National Research Foundation (NRF) University of Pretoria (Pretoria, South Africa) es2026 Paraclinical Sciences PhD Unrestricted SDG-02: Zero hunger SDG-03: Good health and well-being SDG-12: Responsible consumption and production 2021-11-09T12:01:36Z 2021-11-09T12:01:36Z 2021 2020 Thesis * A2021 http://hdl.handle.net/2263/82607 en © 2021 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD sclerostin bone formation sclerosteosis Veterinary science theses SDG-02 Veterinary science theses SDG-03 Veterinary science theses SDG-12 Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title | Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title_full | Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title_fullStr | Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title_full_unstemmed | Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title_short | Effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| title_sort | effect of recombinant mouse sclerostin proteins on bone formation in vitro and in a murine model of sclerosteosis |
| topic | UCTD sclerostin bone formation sclerosteosis Veterinary science theses SDG-02 Veterinary science theses SDG-03 Veterinary science theses SDG-12 |
| url | http://hdl.handle.net/2263/82607 |