Bone homeostasis depends on the resorption of bone by osteoclasts and formation of bone by osteoblasts. Imbalance of this tightly coupled process can cause diseases such as osteoporosis. Thus, the mechanisms that regulate communication between osteoclasts and osteoblasts are critical to bone cell biology. It has been shown that osteoblasts and osteoclasts can communicate with each other through direct cell-cell contact, cytokines and extracellular matrix interaction. Osteoblasts can affect osteoclast formation, differentiation or apoptosis through several pathways, such as OPG/RANKL/RANK, LGR4/RANKL/RANK, Ephrin2/ephB4 and Fas/FasL pathways. Conversely, osteoclasts also influence formation of bone by osteoblasts via the d2 isoform of vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2), complement component 3a, semaphorin 4D or microRNAs. In addition, cytokine released from the resorbed bone matrix, such as TGF-β and IGF-1 also affects the activity of osteoblasts. Several reviews have been performed on the osteoblasts-osteoclasts communication. However, few reviews have shown the research advances in the recent years. In this review we summarized the current knowledge on osteoblast-osteoclast communication.

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Radiation enteritis (RE) is the most common complication of radiotherapy for pelvic irradiation receivers. Herein we investigated the alterations in gut microbial profiles and their association with enteritis in patients undergoing pelvic radiotherapy. Faecal samples were collected from 18 cervical cancer patients during radiotherapy. Microbiota profiles were characterized based on 16S rRNA sequencing using the Illumina HiSeq platform. Epithelial inflammatory response was evaluated using bacterial‐epithelial co‐cultures. Dysbiosis was observed among patients with RE, which was characterized by significantly reduced α‐diversity but increased β‐diversity, relative higher abundance of Proteobacteria and Gammaproteobacteria and lower abundance of Bacteroides . Coprococcus was clearly enriched prior to radiotherapy in patients who later developed RE. Metastat analysis further revealed unique grade‐related microbial features, such as more abundant Virgibacillus and Alcanivorax in patients with mild enteritis. Additionally, using bacterial‐epithelial co‐cultures, RE patient‐derived microbiota induced epithelial inflammation and barrier dysfunction, enhanced TNF‐α and IL‐1β expression compared with control microbiota. Taken together, we define the overall picture of gut microbiota in patients with RE. Our results suggest that dysbiosis of gut microbiota may contribute to development and progression of RE. Gut microbiota can offer a set of biomarkers for prediction, disease activity evaluation and treatment selection in RE.

BackgroundMicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on anti-metastasis strategy. Metastasis-associated in colon cancer-1 (MACC1) has been newly identified to express highly in colorectal cancer (CRC) and promote tumor metastasis through transactivating metastasis-inducing HGF/MET signaling pathway. In this study, we investigated whether miRNA 143 is involved in the regulation of MACC1 and thus plays a functional role in CRC.ResultsUsing both in silico prediction and western blot assay, we found the previously reported tumor suppressive miR-143 targeted MACC1 in CRC. The direct interaction between them was confirmed by 3' UTR luciferase reporter gene. In concordance with the inhibitory effects induced by siRNA mediated knockdown of MACC1, restoration of miR-143 by mimics in SW620 cells significantly attenuated cell growth, migration and invasion. It is notable that combined treatment of miR-143 mimics and MACC1 siRNA induced synergistic inhibitory effects compared to either miR-143 mimics or MACC1 siRNA treatment alone. Conversely, reduction of miR-143 by inhibitors in SW480 cells apparently stimulated these phenotypes. Furthermore, we observed that miR-143 level was inversely correlated with MACC1 mRNA expression in CRC tissues.ConclusionsOur findings newly described miR-143/MACC1 link and provided a potential mechanism for MACC1 dysregulation and contribution to CRC cell invasion. It may help to estimate the therapeutic utility of miR-143 in CRC.

Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma (MM), intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. MicroRNAs (miRs), are noncoding small RNAs that play important roles in the regulation of gene expression, and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone(Dex)-induced drug resistance in MM using the isogenic cell lines, MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization (aCGH) data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely pro-apoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain- and loss- of function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to Dex, whereas anti-miR-221-222 partially restored the Dex sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in MM drug resistance, and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming Dex resistance in patients. The clinical utility of this approach is predicated on the ability of anti-sense miR-221-222 to increase survival while reducing tumor burden, and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of MM. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in MM cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance, and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes.

Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

B-cell malignancies frequently colonizes the bone marrow (BM). The mechanisms responsible for this preferential homing are not entirely known. Using multiple myeloma (MM) as a model of a terminally differentiated B-cell malignancy that selectively colonizes the BM, we demonstrated that BM endothelial cells (BMECs), secrete cyclophilin A (eCyPA), which promotes migration, proliferation, and BM colonization of MM cells via binding to its receptor, CD147, on MM cells. The clinical and translational implications of this work are highlighted by the observation of significantly higher eCyPA levels in BM serum than in peripheral blood (PB) in MM persons, and that eCyPA-CD147 blockade supresses BM-homing and tumor growth in a mouse xenograft model of MM. eCyPA also promoted migration of CLL and LPL cells, two other B-cell malignancies that colonize the BM and express CD147. These findings offer a compelling rationale for exploring the eCyPA-CD147 axis as therapeutic target for these malignancies.