RESUMEN
Bone-fat balance is crucial to maintain bone homeostasis. As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal stem cells (BMSCs) are delicately balanced for their differentiation commitment. However, the exact mechanisms governing BMSC cell fate are unclear. In this study, we discovered that fibroblast growth factor 9 (Fgf9), a cytokine expressed in the bone marrow niche, controlled bone-fat balance by influencing the cell fate of BMSCs. Histomorphology and cytodifferentiation analysis showed that Fgf9 loss-of-function mutation (S99N) notably inhibited bone marrow adipose tissue (BMAT) formation and alleviated ovariectomy-induced bone loss and BMAT accumulation in adult mice. Furthermore, in vitro and in vivo investigations demonstrated that Fgf9 altered the differentiation potential of BMSCs, shifting from osteogenesis to adipogenesis at the early stages of cell commitment. Transcriptomic and gene expression analyses demonstrated that FGF9 upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. Mechanistic studies revealed that FGF9, through FGFR1, promoted adipogenic gene expression via PI3K/AKT/Hippo pathways and inhibited osteogenic gene expression via MAPK/ERK pathway. This study underscores the crucial role of Fgf9 as a cytokine regulating the bone-fat balance in adult bone, suggesting that FGF9 is a potentially therapeutic target in the treatment of osteoporosis.
Asunto(s)
Factor 9 de Crecimiento de Fibroblastos , Células Madre Mesenquimatosas , Osteoporosis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Células Madre Mesenquimatosas/metabolismo , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Factor 9 de Crecimiento de Fibroblastos/genética , Ratones , Osteoporosis/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Femenino , Diferenciación Celular , Osteogénesis/genética , Sistema de Señalización de MAP Quinasas , Transducción de Señal , Ratones Endogámicos C57BL , Adipogénesis , Tejido Adiposo/metabolismoRESUMEN
This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.
Asunto(s)
Linfocitos Infiltrantes de Tumor , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Microambiente TumoralRESUMEN
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The termination of GABA transmission is through the action of GABA transporters (GATs). mGAT4 (encoded by Slc6a11) is another GAT besides GAT1 (encoded by Slc6a1) that functions in GABA reuptake in CNS. Research on the function of mGAT4 is still in its infancy. We developed an mGat4 knockout mouse model (mGat4-/- mice) and performed a series of behavioral analyses for the first time to study the effect of mGat4 on biological processes in CNS. Our results indicated that homozygous mGat4-/- mice had less depression, anxiety-like behavior and more social activities than their wild-type littermate controls. However, they had weight loss and showed motor incoordination and imbalance. Meanwhile, mGat4-/- mice showed increased pain threshold and hypoalgesia behavior in nociceptive stimulus and learning and memory impairments. The expression of multiple components of the GABAergic system including GAD67, GABAA and KCC2 was altered. There is little or no compensatory change in mGat1. In a word, mGat4 may play a key role in normal motor coordination, sensation, emotion, learning and memory and could be the potential target of neurological disorders.
Asunto(s)
Proteínas Transportadoras de GABA en la Membrana Plasmática , Ratones Noqueados , Animales , Masculino , Ratones , Ansiedad/genética , Ansiedad/metabolismo , Conducta Animal , Depresión/genética , Depresión/metabolismo , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Glutamato Descarboxilasa/metabolismo , Glutamato Descarboxilasa/genética , Cotransportadores de K Cl , Ratones Endogámicos C57BL , Simportadores/genética , Simportadores/metabolismoRESUMEN
Spermiogenesis is considered to be crucial for the production of haploid spermatozoa with normal morphology, structure and function, but the mechanisms underlying this process remain largely unclear. Here, we demonstrate that SPEM family member 2 (Spem2), as a novel testis-enriched gene, is essential for spermiogenesis and male fertility. Spem2 is predominantly expressed in the haploid male germ cells and is highly conserved across mammals. Mice deficient for Spem2 develop male infertility associated with spermiogenesis impairment. Specifically, the insufficient sperm individualization, failure of excess cytoplasm shedding, and defects in acrosome formation are evident in Spem2-null sperm. Sperm counts and motility are also significantly reduced compared to controls. In vivo fertilization assays have shown that Spem2-null sperm are unable to fertilize oocytes, possibly due to their impaired ability to migrate from the uterus into the oviduct. However, the infertility of Spem2-/- males cannot be rescued by in vitro fertilization, suggesting that defective sperm-egg interaction may also be a contributing factor. Furthermore, SPEM2 is detected to interact with ZPBP, PRSS21, PRSS54, PRSS55, ADAM2 and ADAM3 and is also required for their processing and maturation in epididymal sperm. Our findings establish SPEM2 as an essential regulator of spermiogenesis and fertilization in mice, possibly in mammals including humans. Understanding the molecular role of SPEM2 could provide new insights into future therapeutic treatment of human male infertility and development of non-hormonal male contraceptives.