MicroRNAs in Bone Metastasis Hesse, Eric; Taipaleenmäki, Hanna
Current osteoporosis reports,
06/2019, Letnik:
17, Številka:
3
Journal Article
Recenzirano
Purpose of Review
This review provides an update on the recent literature describing the role of microRNAs (miRNAs) in cancer formation and bone metastasis. We confined our focus on osteosarcoma, ...breast cancer, prostate cancer, and epithelial-mesenchymal transition.
Recent Findings
In all areas covered, major discoveries on the role of miRNAs in tumorigenesis and metastasis have been made. Novel signaling networks were identified with miRNAs having a central function. Potential improvements in the diagnosis of malignant diseases and the long-term follow-up might become possible by the use of miRNAs. Furthermore, miRNAs also have disease-modifying properties and might emerge as a new class of therapeutic molecules.
Summary
MiRNAs are novel and important regulators of multiple cellular and molecular events. Due to their functions, miRNAs might become useful to improve the diagnosis, follow-up and treatment of cancer, and metastases. Thus, miRNAs are molecules of great interest in translational medicine.
Osteoblast adherence to bone surfaces is important for remodeling bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell ...morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matrices in vitro. Furthermore, Tgif1 acts as a transcriptional repressor of p21-activated kinase 3 ( Pak3 ), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased Pak3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1–34 (PTH 1–34) treatment in vivo in mice. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.
Bone metastases are frequent complications in patients with advanced cancer, which can be fatal or may rapidly impede the quality of life of patients. Current treatments for patients with bone ...metastases are palliative. Therefore, a better understanding of the molecular mechanisms that precede the overt development of skeletal lesions could lead to better therapeutic interventions. In this review, we present evidence that non‐coding RNAs (ncRNAs) such as long ncRNAs, microRNAs, and circular RNAs are emerging as master regulators of bone metastasis formation. We highlight potential opportunities for the therapeutic targeting of ncRNAs. Furthermore, we discuss the possibility that ncRNAs may be used as biomarkers in the context of bone metastases, which might provide insight for improving the response to current bone‐targeting therapies.
LINKED ARTICLES
This article is part of a themed issue on The molecular pharmacology of bone and cancer‐related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc
Purpose of Review
The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia.
Recent Findings
...Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism have been implicated in cancer-induced regeneration defect and muscle loss. Moreover, we review novel in vitro and animal models including promising new drug candidates for bone metastases and cancer cachexia.
Summary
Preservation of bone health could be highly beneficial for maintaining muscle mass and function. Therefore, a better understanding of molecular pathways implicated in bone and muscle crosstalk in metastatic disease may provide new insights and identify new strategies to improve current anticancer therapeutics.
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Intramedullary stabilization is frequently used to treat long bone fractures. Implants usually remain unless complications arise. Since implant removal can become technically very ...challenging with the potential to cause further tissue damage, biodegradable materials are emerging as alternative options. Magnesium (Mg)-based biodegradable implants have a controllable degradation rate and good tissue compatibility, which makes them attractive for musculoskeletal research. Here we report for the first time the implantation of intramedullary nails made of an Mg alloy containing 2% silver (Mg2Ag) into intact and fractured femora of mice. Prior in vitro analyses revealed an inhibitory effect of Mg2Ag degradation products on osteoclast differentiation and function with no impair of osteoblast function. In vivo, Mg2Ag implants degraded under non-fracture and fracture conditions within 210days and 133days, respectively. During fracture repair, osteoblast function and subsequent bone formation were enhanced, while osteoclast activity and bone resorption were decreased, leading to an augmented callus formation. We observed a widening of the femoral shaft under steady state and regenerating conditions, which was at least in part due to an uncoupled bone remodeling. However, Mg2Ag implants did not cause any systemic adverse effects. These data suggest that Mg2Ag implants might be promising for intramedullary fixation of long bone fractures, a novel concept that has to be further investigated in future studies.
Biodegradable implants are promising alternatives to standard steel or titanium implants to avoid implant removal after fracture healing. We therefore developed an intramedullary nail using a novel biodegradable magnesium-silver-alloy (Mg2Ag) and investigated the in vitro and in vivo effects of the implants on bone remodeling under steady state and fracture healing conditions in mice. Our results demonstrate that intramedullary Mg2Ag nails degrade in vivo over time without causing adverse effects. Importantly, radiographs, μCT and bone histomorphometry revealed a significant increase in callus size due to an augmented bone formation rate and a reduced bone resorption in fractures supported by Mg2Ag nails, thereby improving bone healing. Thus, intramedullary Mg2Ag nails are promising biomaterials for fracture healing to circumvent implant removal.
3D imaging of the bone vasculature is of key importance in the understanding of skeletal disease. As blood vessels in bone are deeply encased in the calcified matrix, imaging techniques that are ...applicable to soft tissues are generally difficult or impossible to apply to the skeleton. While canals in cortical bone can readily be identified and characterised in X-ray computed tomographic data in 3D, the soft tissue comprising blood vessels that are putatively contained within the canal structures does not provide sufficient image contrast necessary for image segmentation. Here, we report an approach that allows for rapid, simultaneous visualisation of calcified bone tissue and the vasculature within the calcified bone matrix. Using synchrotron X-ray phase contrast-enhanced tomography we show exemplar data with intracortical capillaries uncovered at sub-micrometre level without the need for any staining or contrast agent. Using the tibiofibular junction of 15 week-old C57BL/6 mice post mortem, we show the bone cortical porosity simultaneously along with the soft tissue comprising the vasculature. Validation with histology confirms that we can resolve individual capillaries. This imaging approach could be easily applied to other skeletal sites and transgenic models, and could improve our understanding of the role the vasculature plays in bone disease.
Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control ...the transcription of defined subsets of genes in various cell systems. In this study we examined the role of BRD4 in promoting lineage-specific gene expression and show that BRD4 is essential for osteoblast differentiation. Genome-wide analyses demonstrate that BRD4 is recruited to the transcriptional start site of differentiation-induced genes. Unexpectedly, while promoter-proximal BRD4 occupancy correlated with gene expression, genes which displayed moderate expression and promoter-proximal BRD4 occupancy were most highly regulated and sensitive to BRD4 inhibition. Therefore, we examined distal BRD4 occupancy and uncovered a specific co-localization of BRD4 with the transcription factors C/EBPb, TEAD1, FOSL2 and JUND at putative osteoblast-specific enhancers. These findings reveal the intricacies of lineage specification and provide new insight into the context-dependent functions of BRD4.
Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt ...activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo. These findings indicate a positive role for miR-218-5p in bone metastasis. Bioinformatic and biochemical analyses revealed a positive correlation between aberrant miR-218-5p expression and activation of Wnt signaling in breast cancer cells. Mechanistically, miR-218-5p targets the Wnt inhibitors Sclerostin (SOST) and sFRP-2, which highly enhances Wnt signaling. In contrast, delivery of antimiR-218-5p decreased Wnt activity and the expression of metastasis-related genes, including bone sialoprotein (BSP/IBSP), osteopontin (OPN/SPP1) and CXCR-4, implicating a Wnt/miR-218-5p regulatory network in bone metastatic breast cancer. Furthermore, miR-218-5p also mediates the Wnt-dependent up-regulation of PTHrP, a key cytokine promoting cancer-induced osteolysis. Antagonizing miR-218-5p reduced the expression of PTHrP and Rankl, inhibited osteoclast differentiation in vitro and in vivo, and prevented the development of osteolytic lesions in a preclinical metastasis model. We conclude that pathological elevation of miR-218-5p in breast cancer cells activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease, suggesting that miR-218-5p could be an attractive therapeutic target for preventing disease progression.
Background A common clinical concern after anterior cruciate ligament reconstruction is the expansion of the bone tunnels as seen radiographically.
The etiology and clinical relevance of this ...phenomenon remain unclear.
Hypothesis Tunnel widening results in an increased anteroposterior translation, and there are specific histologic changes due to osteoclastic
bone resorption associated with this phenomenon.
Study Design Controlled laboratory study.
Methods Thirty sheep (age, 4 months) underwent an anterior cruciate ligament reconstruction using a soft tissue graft. Graft fixation
was achieved using the EndoButton and Suture Washer. Six animals each were sacrificed at 0, 3, 6, 12, and 24 weeks after surgery.
Each anterior cruciate ligamentâreconstructed knee was examined by computed tomography. Anteroposterior translation was determined
using a universal force-moment sensor robot. The bone surrounding the tunnel was evaluated histologically.
Results The prevalence of tunnel enlargement on the femoral side was 77.3%. Animals with tunnel widening did not demonstrate increased
anteroposterior translation. Widening of the femoral tunnel was significantly associated with a higher stiffness of the graft
( P < .05) and hypertrophy of the graft throughout the remodeling process. The histologic evaluation of the bone tunnel walls
demonstrated an increase of bone volume in animals with tunnel enlargement. No statistically significant correlation could
be found between the number of osteoclasts and the presence of tunnel widening.
Conclusion In this large animal model of anterior cruciate ligament reconstruction, animals with significant tunnel widening did not
suffer increased anteroposterior translation. Tunnel widening was associated with a high stiffness of the graft, graft hypertrophy,
and an increase in bone volume of the tunnel wall.
Clinical Relevance The present data correspond to the current opinion in humans that tunnel widening is not associated with knee instability.
Further research is needed to understand the role of graft stiffness, graft hypertrophy, and the increase in bone volume in
this phenomenon.
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