A potential function for MicroRNA-124 in normal and pathological bone conditions.

Cells produce short single-stranded non-coding RNAs (ncRNAs) called microRNAs (miRNAs), which actively regulate gene expression at the posttranscriptional level. Several miRNAs have been observed to exert significant impacts on bone health and bone-related disorders. One of these, miR-124, is observed in bone microenvironments and is conserved across species. It affects bone cell growth and differentiation by activating different transcription factors and signaling pathways. In-depth functional analyses of miR-124 have revealed several physiological and pathological roles exerted through interactions with other ncRNAs. Deciphering these RNA-mediated signaling networks and pathways is essential for understanding the potential impacts of dysregulated miRNA functions on bone biology. In this review, we aim to provide a comprehensive analysis of miR-124's involvement in bone physiology and pathology. We highlight the importance of miR-124 in controlling transcription factors and signaling pathways that promote bone growth. This review reveals therapeutic implications for the treatment of bone-related diseases.

Regulatory and therapeutic implications of competing endogenous RNA network in breast cancer progression and metastasis: A review.

Breast cancer (BC) is a global health concern, and development of diagnostic tools and targeted treatments for BC remains challenging. Therapeutic approaches for BC often involve a combination of surgery, radiation therapy, chemotherapy, targeted therapy, and hormone therapy. In recent years, there has been a growing interest in the role of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), in BC and their therapeutic implications. Various biological processes such as cell proliferation, migration, and apoptosis rely on the activities of these ncRNAs, and their dysregulation has been implicated in BC progression. The regulatory function of the competitive endogenous RNA (ceRNA) network, which comprises lncRNAs, miRNAs, and mRNAs, has been the subject of extensive pathophysiological research. Most lncRNAs serve as molecular sponges for miRNAs and sequester their activities, thereby regulating the expression of target mRNAs and contributing to the promotion or inhibition of BC progression. This review summarizes recent findings on the role of ceRNA networks in BC progression, metastasis, and therapeutic resistance, and highlights the association of ceRNA networks with transcription factors and signaling pathways. Understanding the ceRNA network can lead to the discovery of biomarkers and targeted treatment methods to prevent the spread and metastasis of BC.

In vivo validation of the functional role of MicroRNA-4638-3p in breast cancer bone metastasis.

PURPOSE: Skeletal metastases are increasingly reported in metastatic triple-negative breast cancer (BC) patients. We previously reported that TGF-ß1 sustains activating transcription factor 3(ATF3) expression and is required for cell proliferation, invasion, and bone metastasis genes. Increasing studies suggest the critical regulatory function of microRNAs (miRNAs) in governing BC pathogenesis. TGF-ß1 downregulated the expression of miR-4638-3p, which targets ATF3 in human BC cells (MDA-MB-231). In the present study, we aimed to identify the functional role of miR-4638-3p in BC bone metastasis by the caudal artery injection of the MDA-MB-231 cells overexpressing mir-4638 in the mice. METHODS: MDA-MB-231 cells overexpressing miR-4638 were prepared by stable transfections. Reverse transcriptase quantitative PCR was carried out to determine the expression of endogenous miR-4638-3p and bone resorption marker genes. X-ray, micro-CT, and Hematoxylin & Eosin studies were used to determine osteolytic lesions, trabecular structure, bone mineral density, and micrometastasis of cells. RESULTS: The mice injected with MDA-MB-231 cells overexpressing miR-4638-3p decreased the expression of bone resorption marker genes, compared to MDA-MB-231 cells injection. Reduced osteolytic lesions and restored bone density by MDA-MB-231 cells overexpressing miR-4638-3p were observed. Similarly, the mice injected with MDA-MB-231 cells overexpressing miR-4638-3p showed a better microarchitecture of the trabecular network. A few abnormal cells seen in the femur of MDA-MB-231 cells-injected mice were not found in MDA-MB-231 cells overexpressing miR-4638. CONCLUSION: The identified functional role of ATF3 targeting miR-4638-3p in BC bone metastasis in vivo suggests its candidature as BC therapeutics in the future.

MicroRNAs mediated interaction of tumor microenvironment cells with breast cancer cells during bone metastasis.

Breast cancer (BC) bone metastasis is primarily osteolytic and has limited therapeutic options. Metastasized BC cells prime the secondary environment in bone by forming a tumor niche, which favors their homing and colonization. The tumor microenvironment (TME) is primarily generated by the cancer cells. Bone TME is an intricate network of multiple cells, including altered bone, tumor, stromal, and immune cells. Recent findings highlight the significance of small non-coding microRNAs (miRNAs) in influencing TME during tumor metastasis. MiRNAs from TME-resident cells facilitate the interaction between the tumor and its microenvironment, thereby regulating the biological processes of tumors. These miRNAs can serve as oncogenes or tumor suppressors. Hence, both miRNA inhibitors and mimics are extensively utilized in pre-clinical trials for modulating the phenotypes of tumor cells and associated stromal cells. This review briefly summarizes the recent developments on the functional role of miRNAs secreted directly or indirectly from the TME-resident cells in facilitating tumor growth, progression, and metastasis. This information would be beneficial in developing novel targeted therapies for BC.

Circ_CUX1/miR-130b-5p/p300 axis for parathyroid hormone-stimulation of Runx2 activity in rat osteoblasts: A combined bioinformatic and experimental approach.

Parathyroid hormone (PTH) regulates the expression of bone remodeling genes by enhancing the activity of Runx2 in osteoblasts. p300, a histone acetyltransferase, acetylated Runx2 to activate the expression of its target genes. PTH stimulated the expression of p300 in rat osteoblastic cells. Increasing studies suggested the potential of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and circular RNAs (circRNAs), in regulating gene expression under both physiological and pathological conditions. In this study, we hypothesized that PTH regulates Runx2 activity via ncRNAs-mediated p300 expression in rat osteoblastic cells. Bioinformatics and experimental approaches identified PTH-upregulation of miR-130b-5p and circ_CUX1 that putatively target p300 and miR-130b-5p, respectively. An antisense-mediated knockdown of circ_CUX1 was performed to determine the sponging activity of circ_CUX1. Knockdown of circ_CUX1 promoted miR-130b-5p activity and reduced p300 expression, resulting in decreased Runx2 acetylation in rat osteoblastic cells. Further, bioinformatics analysis identified the possible signaling pathways that regulate Runx2 activity and osteoblast differentiation via circ_CUX1/miR-130b-5p/p300 axis. The predicted circ_CUX1/miR-130b-5p/p300 axis might pave the way for better diagnostic and therapeutic approaches for bone-related diseases.

Regulation of Wnt signaling by non-coding RNAs during osteoblast differentiation.

Bone is a rigid, mineralized connective tissue that constitutes part of the skeleton in most vertebrate animals. Bone remodeling is a complex process that involves the coordination of ossification and bone resorption activities by osteoblasts and osteoclasts, respectively, resulting in maintaining bone mass. This process involves several growth factors/cytokines and hormones regulating the various signaling pathways. Wnt is one of the major molecular signaling pathways that positively regulate the osteogenic differentiation of mesenchymal stem cells. Dysregulation in the Wnt signaling leads to serious bone-related disorders like osteoporosis and osteosclerosis. Recently, several studies reported the critical role of non-coding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, in the regulation of bone homeostasis via modulating the Wnt signaling cascade. This review summarizes the importance of such ncRNAs in mediating the Wnt cascade and its effect on osteoblast differentiation. Understanding the regulatory role of these ncRNAs would serve as a novel therapeutic strategy for treating bone-related disorders.

Role of p300, a histone acetyltransferase enzyme, in osteoblast differentiation.

Bone is a dynamic and tough connective tissue that undergoes constant remodeling throughout life. Bone-forming osteoblasts respond to various hormones, cytokines, and growth factors, and synthesize extracellular matrix components. Runx2 (Runt-related transcription factor 2), a bone transcription factor, is essential for ossification by stimulating the expression of osteoblast differentiation marker genes, including type I collagen, alkaline phosphatase, and osteocalcin. Coactivators, such as p300, CBP (CREB-binding protein), and PCAF (p300/CBP associated factor) tightly regulate osteoblast differentiation via Runx2. There is growing evidence indicating the role of p300, which possesses histone acetyltransferase (HAT) activity, in regulating histones and transcription factors such as Runx2 during osteoblast differentiation. In this review, we aim to delineate the role of p300 at the molecular level, emphasizing the importance of its HAT activity during osteoblast differentiation. Furthermore, this review intends to highlight the regulation of p300 at multiple levels, including post-translational and ncRNAs, that might exert an indirect influence on bone formation.