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Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch between the osteoblastic and osteoclastic phases have not been fully elucidated. Here, we identify a specific subset of mature osteoblast-derived extracellular vesicles that inhibit bone formation and enhance osteoclastogenesis. Intravital imaging reveals that mature osteoblasts secrete and capture extracellular vesicles, referred to as small osteoblast vesicles (SOVs). Co-culture experiments demonstrate that SOVs suppress osteoblast differentiation and enhance the expression of receptor activator of NF-κB ligand, thereby inducing osteoclast differentiation. We also elucidate that the SOV-enriched microRNA miR-143 inhibits Runt-related transcription factor 2, a master regulator of osteoblastogenesis, by targeting the mRNA expression of its dimerization partner, core-binding factor β. In summary, we identify SOVs as a mode of cell-to-cell communication, controlling the dynamic transition from bone-forming to bone-resorbing phases in vivo. Bone remodeling involves a switch between bone formation and resorption, but the mechanisms is unclear. Here, the authors show that intercellular communication via extracellular vesicles secreted by mature osteoblasts is a key factor for the switching, via a microRNA-mediated mechanism.

Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg 2+ -permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2 -deficient mice. We generate kidney-specific Trpm6 -deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of β-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure. Circadian variation of blood pressure, with higher values in the active period, is associated with the risk of fatal cardiovascular events. Here, we show the importance of renal TRPM6, a Magnesium-permeable cation channel, in raising blood pressure by stimulating renin secretion.

Osteoclasts have a unique bone-destroying capacity, playing key roles in steady-state bone remodeling and arthritic bone erosion. Whether the osteoclasts in these different tissue settings arise from the same precursor states of monocytoid cells is presently unknown. Here, we show that osteoclasts in pannus originate exclusively from circulating bone marrow-derived cells and not from locally resident macrophages. We identify murine CX 3 CR1 hi Ly6C int F4/80 + I-A + /I-E + macrophages (termed here arthritis-associated osteoclastogenic macrophages (AtoMs)) as the osteoclast precursor-containing population in the inflamed synovium, comprising a subset distinct from conventional osteoclast precursors in homeostatic bone remodeling. Tamoxifen-inducible Foxm1 deletion suppressed the capacity of AtoMs to differentiate into osteoclasts in vitro and in vivo. Furthermore, synovial samples from human patients with rheumatoid arthritis contained CX 3 CR1 + HLA-DR hi CD11c + CD80 − CD86 + cells that corresponded to mouse AtoMs, and human osteoclastogenesis was inhibited by the FoxM1 inhibitor thiostrepton, constituting a potential target for rheumatoid arthritis treatment. Osteoclasts are a monocytoid cell with unique bone-remodeling capability. Ishii and colleagues demonstrate that the transcription factor FoxM1 is important for the differentiation of osteoclasts associated with pathological remodeling of the rheumatoid joint.

The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology. In cancer it is assumed that microRNAs recognise and regulate their targets uniformly. Here, the authors show that in gastrointestinal cancers methylation of microRNAs may impact their stability, and that levels of microRNA methylation are distinct in pancreatic cancer patients compared to healthy controls with potential diagnostic implications.

Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and clinicopathological studies are therefore needed. Here, we investigated the role of family with sequence similarity 111 member B (FAM111B), which is highly expressed in papillary‐predominant LUAD; however, its role in cancer is unclear. An immunohistochemical analysis confirmed that papillary‐predominant adenocarcinomas exhibited higher expression of FAM111B, compared with lepidic‐predominant adenocarcinomas. Additionally, FAM111B expression was significantly correlated with clinical progression. In vitro functional analyses using FAM111B‐knockout cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of KRAS‐driven LUAD under serum‐starvation conditions. Furthermore, FAM111B regulated cyclin D1‐CDK4‐dependent cell cycle progression by degradation of p16. In summary, we revealed the clinical importance of FAM111B in human tumor tissues, as well as its function as a degradative enzyme. Therefore, FAM111B has potential as a clinicopathological prognostic marker for LUAD. We screened family with sequence similarity 111 member B (FAM111B), the precise functional role of which in cancers is not clear, as the molecule is highly expressed in papillary‐predominant lung adenocarcinoma. Immunohistochemical analysis confirmed that papillary‐predominant adenocarcinoma had higher expression of FAM111B compared with lepidic‐predominant adenocarcinoma, and FAM111B expression levels were significantly correlated with patients’ clinical progression. In vitro functional analyses using FAM111B‐knockout (FAM111B‐KO) cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of LUAD with the KRAS mutation, specifically under the conditions of serum starvation, and it was revealed that FAM111B negatively regulates CyclinD1‐CDK4‐dependent cell cycle progression by functioning as a degrading enzyme to control p16 expression level.

Background It is important to establish cancer stem cell (CSC)-targeted therapies to eradicate cancer. As it is a CSC marker, we focused on Kruppel-like factor 5 ( KLF5 ) in this study. Methods We searched for candidate microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines. Results We identified one promising miRNA, miR-4711-5p, that downregulated KLF5 expression by direct binding. This miRNA suppressed cell proliferation, migration and invasion ability, as well as stemness, including decreased stem cell marker expression, reactive oxygen species activity and sphere formation ability. MiR-4711-5p inhibited the growth of DLD-1 xenografts in nude mice with no adverse effects. We found that miR-4711-5p provoked G1 arrest, which could be attributed to direct binding of miR-4711-5p to TFDP1 (a heterodimeric partner of the E2F family). Our findings also suggested that direct binding of miR-4711-5p to MDM2 could upregulate wild-type p53, leading to strong induction of apoptosis. Finally, we found that miR-4711-5p had a potent tumour-suppressive effect compared with a putative anti-oncomiR, miR-34a, in tumour cell cultures derived from five patients with colorectal cancer. Conclusions Our data suggest that miR-4711-5p could be a promising target for CSC therapy.

Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast–osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism. The mechanism by which parathyroid hormone mediates the switch from bone resorption to bone formation is unclear. Here, the authors show that SLPI regulates the communication between osteoblasts and osteoclasts to promote the anabolic effect of parathyroid hormone.

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell–cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12 - CXCR4 . The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules. Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases.

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H + -ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism. The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.

Traumatic brain injury (TBI) can alter various immune functions, including immunosuppression, and constitutes a risk factor for nosocomial infections and organ dysfunction. Although TBI can induce a decline in immune cell function, the detailed mechanisms remains to be elucidated. We aim to explore transcriptional signatures associated with post-TBI immune alterations in a pilot cohort using a comprehensive transcriptome analysis of immune cells. Three patients with traumatic brain injury and acute subdural hematoma were admitted to our hospital. We focused on three major subsets of immune cells responsible for the immune response: CD4 + T cells, CD8 + T cells, and monocytes. We evaluated the changes in immune function after injury using comprehensive transcriptome analysis. Blood samples were collected immediately after admission and one week later, and the data were compared with those of healthy volunteers. CD4 + , CD8 + T cells, and monocytes, the expression of pathways involved in cellular metabolism—including oxidative phosphorylation, mTORC1 signaling, MYC targets V1 and V2, and the unfolded protein response—was downregulated on day 7 compared with day 1. These findings suggest a transition from marked immune activation and metabolic upregulation on day 1 to an attenuated immune response by day 7. In CD4 + T cells, pathways associated with tissue remodeling and repair, such as hedgehog signaling and epithelial–mesenchymal transition, were upregulated from days 1 to 7, indicating a shift from inflammatory responses toward inflammation resolution and tissue repair. In this pilot study, comprehensive transcriptome profiling suggests time-dependent transcriptional shifts in CD4⁺ T cells, CD8⁺ T cells, and monocytes after TBI. These findings should be interpreted as hypothesis-generating and provide a framework for larger, confirmatory studies.