Resveratrol facilitates bone marrow mesenchymal stem cells (BMSCs) differentiation to prevent osteoporosis via restraining of secreted frizzled-related protein 1 expression

Secreted frizzled-related protein 1 (SFRP1) is associated with cell differentiation, and its expression can be modulated by resveratrol. However, their impacts on bone marrow mesenchymal stem cells (BMSCs)-induced osteogenesis and ovariectomy-triggered bone loss remain unclear. Therefore, we in this study aimed to dissect the regulation of resveratrol on SFRP1, along with its sequential effects on differentiation and osteoporosis prevention of BMSCs. The SFRP1 expression in the ovariectomized (OVX) mice-originated bone tissues, BMSCs and bone marrow-derived macrophages (BMMs), during their differentiation towards osteoblasts and chondrocytes, was quantified by qRT-PCR and Western-blot. SFRP1-siRNA was applied for studying its influence on osteogenesis of BMSCs. Additionally, we evaluated the impacts of resveratrol on OVX mice and SFRP1 expression. SFRP1 was significantly up-regulated in the OVX mice-derived bone tissues and BMSCs, but gradually decreased during osteogenesis. Its expression was not significantly changed in BMSCs during their differentiation towards osteoclasts or in BMMs. The knockout of SFRP1 significantly improved mineralization potentiality, alkaline phosphatase activity and expression of several osteoblast-specific genes. Moreover, the bone loss was ameliorated in OVX mice treated with resveratrol, whose therapeutic effects were achieved by facilitating the expression of osteogenesis-associated genes while suppressing the SFRP1 expression. We also observed that the SFRP1 exerted a negative effect on osteogenesis of BMSCs and estrogen deficiency-induced osteoporosis, enabling itself to be an indicator of osteogenesis and also a molecular target for PMOP treatment. Resveratrol is a suppressor of SFRP1that can be applied as an active ingredient for treating PMOP.

sFRP1 Expression Regulates Wnt signaling in Chronic Myeloid Leukemia K562 Cells

Background: Wnt signaling cascades play important roles in cell fate decisions and their deregulation has been documented in many diseases, including malignant tumors and leukemia. One mechanism of aberrant Wnt signaling is the silencing of Wnt inhibitors through epigenetic mechanisms. The sFRPs are one of the most studied Wnt inhibitors; and the sFRP1 loss is known in many hematological malignancies. Therefore, we aimed to compare the expression of Wnt related genes in the presence and absence of sFRP1 in chronic myeloid leukemia (CML) cell line. Objective: It is important to understand how sFRP1 and sFRP1 perform on CML to design new agents and strategies for resistant and advanced forms of CML. Materials and Methods: We used K562 cells, which normally do not express sFRP1 and its sFRP1 expressing subclone K562s. Total RNA was isolated from K562 and K562s cell lines end converted cDNA. PCR Array experiments performed using Human Wnt Signaling Pathway Plus RT2 Profiler™ kit. Wnt signaling pathway activation was studied by western blot for downstream signaling targets. Results: The WNT3, LRP6, PRICKLE1 and BTRC expressions were significantly decreased in the presence of sFRP1; while WNT5B increased. The sFRP1 expression inhibited stabilization of total β-catenin protein and downstream effector phosphorylation of noncanonical Wnt/PCP signaling; whereas Ca2+/PKC signaling remained active. Conclusion: The results suggest that sFRP1 could be a promising therapeutic anticancer agent. Defining these pathway interactions is crucial to design new agents resistant and advanced forms of CML.

Secreted Frizzled-Related Protein 1 as a Biomarker against Incomplete Age-Related Lobular Involution and Microcalcifications’ Development

As a downregulator of the Wnt signaling pathway, SFRP1 is involved in several components of the age-related lobular involution process such as inflammation, apoptosis, and adipogenesis. Because microcalcifications are associated with inflammation, we aimed to demystify the cross talk between SFRP1, inflammatory markers, and microcalcifications by assessing SFRP1 expression (immunohistochemistry) in a cohort of 162 women with different degrees of lobular involution. SFRP1 expression was inversely associated with the degree of lobular involution (OR = 0.84; p-value < 0.01). SFRP1 expression, age at mastectomy, and waist circumference taken together predicted the degree of lobular involution (AUC = 78.1). This predictive model was best in patients with microcalcifications (AUC = 81.1) and in parous women (AUC = 87.8). SFRP1 expression was correlated with leptin (rho = 0.32), TNF-α (rho = 0.21), and IL-6 (rho = 0.21) expression by epithelial cells (all p-values <0.001). SFRP1 expression was lower in nulliparous women with involuted breast tissue compared with parous women with involuted breast tissue (Δmean = −2.31; p-value < 0.01) and was higher in nulliparous women with microcalcifications compared with nulliparous women without microcalcifications (Δmean = 2.4; p-value < 0.05). In this study, we highlighted two SFRP1-based predictive models for incomplete lobular involution and the development of microcalcifications and identified two distinct inflammatory profiles associated with age-related lobular involution in parous and nulliparous women.

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.

Silencing microRNA-27a inhibits proliferation and invasion of human osteosarcoma cells through the SFRP1-dependent Wnt/β-catenin signaling pathway

Osteosarcoma is the most common malignant tumor of bone with a high potential for metastasis. Importantly, microRNA-27a (miR-27a) is involved in the progression of osteosarcoma. The present study aims to discuss the effects of miR-27a and its target gene secreted frizzled related protein 1 (SFRP1) on proliferation and invasion of human osteosarcoma cells via Wnt/β-catenin signaling pathway. The expression of miR-27a and SFRP1 in osteosarcoma tissues and cells was detected, followed by identification of their relations. Subsequently, miR-27a mimic, miR-27a inhibitor, or siRNA against SFRP1 were introduced into cells (HOS and U2OS) to investigate their role in cell proliferation and invasion. The expression of Wnt/β-catenin signaling pathway-related gene was analyzed to further uncover the regulatory mechanism of miR-27a. The osteosarcoma tissues and cells exhibited elevated miR-27 expression and reduced SFRP1 expression. SFRP1 was verified to be a target gene of miR-27a. Meanwhile, silenced miR-27a inhibited proliferation and invasion of human osteosarcoma cells. Finally, silencing miR-27a inhibited the activation of Wnt/β-catenin signaling pathway, evidenced by reduced β-catenin expression. Our study draws a conclusion that silencing miR-27a dampens osteosarcoma progression, which might be achieved through the inactivation of the Wnt/β-catenin signaling pathway by up-regulating SFRP1.