AIMSEvidence suggests alterations of thyroid hormone levels can disrupt normal bone development. Most data suggest the major targets of thyroid hormones to be the Htra1/Igf1 pathway. Recent discovery by our group suggests involvement of targets WNT pathway, specifically overexpression of antagonist Sfrp4 in the presence of exogenous thyroid hormone.MAIN METHODSHere we aimed to model these interactions in vitro using primary and isotype cell lines to determine if thyroid hormone drives increased Sfrp4 expression in cells relevant to craniofacial development. Transcriptional profiling, bioinformatics interrogation, protein and function analyses were used.KEY FINDINGSAffymetrix transcriptional profiling found Sfrp4 overexpression in primary cranial suture derived cells stimulated with thyroxine in vitro. Interrogation of the SFRP4 promoter identified multiple putative binding sites for thyroid hormone receptors. Experimentation with several cell lines demonstrated that thyroxine treatment induced Sfrp4 expression, demonstrating that Sfrp4 mRNA and protein levels are not tightly coupled. Transcriptional and protein analyses demonstrate thyroid hormone receptor binding to the proximal promoter of the target gene Sfrp4 in murine calvarial pre-osteoblasts. Functional analysis after thyroxine hormone stimulation for alkaline phosphatase activity shows that pre-osteoblasts increase alkaline phosphatase activity compared to other cell types, suggesting cell type susceptibility. Finally, we added recombinant SFRP4 to pre-osteoblasts in combination with thyroxine treatment and observed a significant decrease in alkaline phosphatase positivity.SIGNIFICANCETaken together, these results suggest SFRP4 may be a key regulatory molecule that prevents thyroxine driven osteogenesis. These data corroborate clinical findings indicating a potential for SFRP4 as a diagnostic or therapeutic target for hyperostotic craniofacial disorders.

01 Apr 2019·The International Journal of Biochemistry & Cell BiologyQ2 · BIOLOGY

Epigenetic demethylation of sFRPs, with emphasis on sFRP4 activation, leading to Wnt signalling suppression and histone modifications in breast, prostate, and ovary cancer stem cells

Q2 · BIOLOGY

Article

Author: Newsholme, Philip ; Deshmukh, Abhijeet ; Arfuso, Frank ; Dharmarajan, Arun

The expression and levels of secreted frizzled-related proteins (sFRPs), important Wnt signalling antagonists, have been reported to be reduced in various cancers, and are associated with disease progression and poor prognosis. During tumour development, all sFRP (1, 2, 3, 4, and 5) genes are hypermethylated, causing transcriptional silencing. sFRPs have an ability to sensitize tumour cells to chemotherapeutic drugs, enhancing cell death. Reduced Wnt signalling is associated with loss of cancer stem cell (CSC) viability. We investigated the possible involvement of methylation-mediated silencing of the sFRP gene family in CSCs derived from breast, prostate, and ovarian tumour cell lines. Real-time RT-PCR studies indicated that loss or downregulation of sFRP (1-5) expression in tumours is associated with promoter hypermethylation. Additionally, CSCs derived from all tumour cell lines with sFRP (1-5) promotor hypermethylation expressed sFRP (1-5) mRNA after treatment with 5-Azacytidine (5-Aza), especially sFRP4, implying that DNA methylation is the predominant epigenetic mechanism for sFRP (1-5) silencing. Furthermore, post-translational modification (PTM) in total and histone proteins was observed post 5-Aza and sFRP4 treatment. Protein levels of Wnt downstream signalling components (GSK3β, active β-catenin, and phospho β-catenin) and epigenetic factors of histones (acetyl histone H3, and H3K27me3) affecting PTM were analysed. Our findings suggest that downregulation of sFRP4 expression in endocrine-related cancers can be attributed to aberrant promoter hypermethylation in conjugation with histone modification, and indicate the important role of methylation-induced gene silencing of sFRP4 in survival and proliferation of CSCs derived from these cancers.

01 Nov 2010·Tissue Engineering Part AQ2 · MEDICINE

Secreted Frizzled Related Protein 4 Reduces Fibrosis Scar Size and Ameliorates Cardiac Function After Ischemic Injury

Q2 · MEDICINE

Article

Author: Matsushima, Kentaro ; Ikeda, Keiko ; Jakt, Lars Martin ; Nishishita, Naoki ; Takenaka, Chiemi ; Ikada, Yoshito ; Sawa, Yoshiki ; Mori, Hajime ; Kawamata, Shin ; Suyama, Takashi

Expression of the Wnt modulator secreted frizzled related protein 4 (Sfrp4) is upregulated after heart ischemic injury. We show that intramuscular administration of recombinant Sfrp4 to rat heart ischemic injury and recanalization models prevents further deterioration of cardiac function after the ischemic injury. The effect of Sfrp4 persisted for at least 20 weeks when Sfrp4 was administered in a slow release system (Sfrp4-polyhedra) to both acute and subacute ischemic models. The histology of the dissected heart showed that the cardiac wall was thicker and the area of acellular scarring was smaller in Sfrp4-treated hearts than in controls. Increased amounts of both the inactive serine 9-phosphorylated form of glycogen synthase kinase (GSK)-3β and the active form of β-catenin were observed by immunohistology 3 days after lateral anterior descendant ligation in control, but not in Sfrp4-treated hearts. All together, we show that administration of Sfrp4 interferes with canonical Wnt signaling that could mediate the formation of acellular scar and consequently contributes to the prevention of aggravation of cardiac function.

100 Deals associated with sFRP-4

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	IN	Anna University	-
Neoplasms	Discovery	AU	The University of Western Australia	-

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