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The role of SOSTDC1 in interactions between myeloma and cells of osteoblast lineage

Faraahi, Zahra Fahimeh ZF (2014) The role of SOSTDC1 in interactions between myeloma and cells of osteoblast lineage. PhD thesis, University of Sheffield.

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Abstract

Rationale and Hypothesis: Multiple myeloma (MM) is characterised by destructive bone disease, mediated by an increase in osteoclastic bone resorption and impaired osteoblastic bone formation. The canonical Wingless-type (Wnt) and Bone Morphogenic Protein (BMP) signalling pathways have both been implicated in the regulation of bone formation. Our data show that SOSTDC1 is upregulated in the bone marrow (BM) of mice with osteolytic bone disease associated with myeloma. It is unclear whether SOSTDC1 regulates signalling in bone directly, and also which cells in the BM express SOSTDC1. We hypothesise that SOSTDC1 disrupts Wnt and BMP signalling in bone and is expressed by both myeloma cells (MC) and osteoblasts (OB) as a result of myeloma cell/osteoblast interaction. The objectives of this study were to (i) assess the effect of SOSTDC1 on mouse primary osteoblast (pOB) differentiation in the presence of activated BMP and Wnt signalling and (ii) to determine the conditions under which myeloma cells express SOSTDC1. Materials and Methods: Mouse pOB were treated with recombinant SOSTDC1 protein, in the presence or absence of BMP2, BMP7 or Wnt3a. The effects of SOSTDC1 treatment on BMP and Wnt signalling were determined by measuring BMP-activated Smad phosphorylation and phosphorylated β-catenin respectively, using western blot. qPCR was used to assess the effects of SOSTDC1 on the regulation of genes involved in pOB differentiation. Flow-cytometry, immunofluorescence and western blot analysis were used to determine the distribution of SOSTDC1 in MC/OB cultures and co-cultures. Results: SOSTDC1 suppressed BMP2- and BMP7-induced Smad phosphorylation and also Wnt3a-induced β-catenin phosphorylation in pOB (P<0.05). Both Runx2a and total β-catenin expression (qPCR) were reduced following treatment with SOSTDC1, suggesting that SOSTDC1 suppresses Wnt3a-induced pOB differentiation (P<0.05). Flow-cytometry, immunofluorescence and western blot data all suggest that SOSTDC1 is switched on in OB and increased in MC, when these two cells are cultured together. Conclusions: Our findings suggest that increased SOSTDC1 levels may result from OB/MC contact and that this may result in suppression of OB differentiation. Taken together these results suggest that targeting SOSTDC1 may reduce osteolytic bone disease observed in MM.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.638948
Depositing User: Dr Zahra Fahimeh faraahi
Date Deposited: 03 Mar 2015 08:43
Last Modified: 12 Oct 2018 09:22
URI: http://etheses.whiterose.ac.uk/id/eprint/7542

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