Abstract The Hippo signalling pathway is a conserved kinase cascade that orchestrates diverse cellular processes, such as proliferation, apoptosis, lineage commitment and stemness. With the onset of society ages, research on skeletal aging‐mechanics‐bone homeostasis has exploded. In recent years, aging and mechanical force in the skeletal system have gained groundbreaking research progress. Under the regulation of mechanics and aging, the Hippo signalling pathway has a crucial role in the development and homeostasis of bone. We synthesize the current knowledge on the role of the Hippo signalling pathway, particularly its downstream effectors yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ), in bone homeostasis. We discuss the regulation of the lineage specification and function of different skeletal cell types by the Hippo signalling pathway. The interactions of the Hippo signalling pathway with other pathways, such as Wnt, transforming growth factor beta and nuclear factor kappa‐B, are also mentioned because of their importance for modulating bone homeostasis. Furthermore, YAP/TAZ have been extensively studied as mechanotransducers. Due to space limitations, we focus on reviewing how mechanical forces and aging influence cell fate, communications and homeostasis through a dysregulated Hippo signalling pathway.
Abstract Background Most of the microRNAs (MiRs) involved in myogenesis are transcriptional regulated. The role of MiR biogenesis in myogenesis has not been characterized yet. RNA‐binding protein Musashi 2 (Msi2) is considered to be one of the major drivers for oncogenesis and stem cell proliferation. The functions of Msi2 in myogenesis have not been explored yet. We sought to investigate Msi2‐regulated biogenesis of MiRs in myogenesis and muscle stem cell (MuSC) ageing. Methods We detected the expression of Msi2 in MuSCs and differentiated myotubes by quantitative reverse transcription PCR (RT‐qPCR) and western blot. Msi2‐binding partner human antigen R (HuR) was identified by immunoprecipitation followed by mass spectrometry analysis. The cooperative binding of Msi2 and HuR on MiR7a‐1 was analysed by RNA immunoprecipitation and electrophoresis mobility shift assays. The inhibition of the processing of pri‐MiR7a‐1 mediated by Msi2 and HuR was shown by Msi2 and HuR knockdown. Immunofluorescent staining, RT‐qPCR and immunoblotting were used to characterize the function of MiR7a‐1 in myogenesis. Msi2 and HuR up‐regulate cryptochrome circadian regulator 2 (Cry2) via MiR7a‐1 was confirmed by the luciferase assay and western blot. The post‐transcriptional regulatory cascade was further confirmed by RNAi and overexpressing of Msi2 and HuR in MuSCs, and the in vivo function was characterized by histopathological and molecular biological methods in Msi2 knockout mice. Results We identified a post‐transcription regulatory cascade governed by a pair of RNA‐binding proteins Msi2 and HuR. Msi2 is enriched in differentiated muscle cells and promotes MuSC differentiation despite its pro‐proliferation functions in other cell types. Msi2 works synergistically with another RNA‐binding protein HuR to repress the biogenesis of MiR7a‐1 in an Msi2 dose‐dependent manner to regulate the translation of the key component of the circadian core oscillator complex Cry2. Down‐regulation of Cry2 (0.6‐fold, vs. control, P < 0.05) mediated by MiR7a‐1 represses MuSC differentiation. The disruption of this cascade leads to differentiation defects of MuSCs. In aged muscles, Msi2 (0.3‐fold, vs. control, P < 0.01) expression declined, and the Cry2 protein level also decreases (0.5‐fold, vs. control, P < 0.05), suggesting that the disruption of the Msi2‐mediated post‐transcriptional regulatory cascade could attribute to the declined ability of muscle regeneration in aged skeletal muscle. Conclusions Our findings have identified a new post‐transcriptional cascade regulating myogenesis. The cascade is disrupted in skeletal muscle ageing, which leads to declined muscle regeneration ability.
We extracted articular chondrocytes from Zmpste24f/f mice and infected them with GFP/Cre lentivirus, and obtained RNA from both Control (GFP-treated group) and CKO (Cre-treated group) groups of cells for transcriptome sequencing. (fold change greater than 1.5 and P-value less than 0.05)
The skeleton is an important structural and metabolic organ in human body, while aging is the physiological basis for degenerative skeletal diseases. China has the largest aging population in the world and faces great challenges in preventing and managing diseases related to skeletal aging. To address these challenges, the Aging China Biomarkers Consortium (ABC) has reached an expert consensus on biomarkers of skeletal aging by synthesizing the literature and insights from scientists and clinicians. The consensus provides a comprehensive assessment of biomarkers associated with skeletal aging and proposes a systematic framework that categorizes biomarkers into three dimensions, namely, functional, structural, and humoral dimensions. Within each dimension, the ABC recommended clinical and evidential research-based biomarkers for physiological aging and degenerative pathologies of the skeleton. This expert consensus aims to lay the foundation for future studies to assess the prediction, diagnosis, early warning, and treatment of diseases associated with skeletal aging, with the ultimate goal of improving the skeletal health of elderly populations in China and around the world.
Abstract Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of therapeutic drugs more challenging. The deficiency of ZMPSTE24 could induce Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder of rapid aging. However, the relationship between HGPS and OA remains unclear. Our results found that the expression of Zmpste24 was decreased in the articular cartilage during the aging process. Zmpste24 knockout mice, Prx1-Cre; Zmpste24 fl/fl mice and Col2-CreERT2; Zmpste24 fl/fl mice displayed OA phenotype. Loss of Zmpste24 in articular cartilage could exacerbate the occurrence and development of osteoarthritis. Transcriptome sequencing revealed that deletion of Zmpste24 or accumulation of progerin affects chondrocyte metabolism, inhibits cell proliferation and promotes cell senescence. Using this animal model, we elucidate the upregulation of H3K27me3 during chondrocyte senescence and discover the molecular mechanism by which lamin A mutant stabilizes EZH2 expression. The construction of aging-induced osteoarthritis models and the elucidation of the signaling pathways and molecular mechanisms of articular chondrocyte senescence would benefit the discovery and development of new drugs for OA.
The regulation of fatty acid metabolism is crucial for milk flavor and quality. Therefore, it is important to explore the genes that play a role in fatty acid metabolism and their mechanisms of action. The RNA-binding protein Musashi2 (MSI2) is involved in the regulation of numerous biological processes and plays a regulatory role in post-transcriptional translation. However, its role in the mammary glands of dairy cows has not been reported. The present study examined MSI2 expression in mammary glands from lactating and dry milk cows. Experimental results in bovine mammary epithelial cells (BMECs) showed that MSI2 was negatively correlated with the ability to synthesize milk fat and that MSI2 decreased the content of unsaturated fatty acids (UFAs) in BMECs. Silencing of Msi2 increased triglyceride accumulation in BMECs and increased the proportion of UFAs. MSI2 affects TAG synthesis and milk fat synthesis by regulating fatty acid synthase (FASN). In addition, RNA immunoprecipitation experiments in BMECs demonstrated for the first time that MSI2 can bind to the 3′-UTR of FASN mRNA to exert a regulatory effect. In conclusion, MSI2 affects milk fat synthesis and fatty acid metabolism by regulating the triglyceride synthesis and UFA content through binding FASN.
Excessive neuroinflammation after spinal cord injury (SCI) is a major hurdle during nerve repair. Although proinflammatory macrophage/microglia-mediated neuroinflammation plays important roles, the underlying mechanism that triggers neuroinflammation and aggravating factors remain unclear. The present study identified a proinflammatory role of semaphorin3C (SEMA3C) in immunoregulation after SCI. SEMA3C expression level peaked 7 days post-injury (dpi) and decreased by 14 dpi.
Bone fracture is repaired predominantly through endochondral ossification. However, the regulation of endochondral ossification by key factors during fracture healing remains largely enigmatic. Here, we identify histone modification enzyme LSD1 as a critical factor regulating endochondral ossification during bone regeneration. Loss of LSD1 in Prx1 lineage cells severely impaired bone fracture healing. Mechanistically, LSD1 tightly controls retinoic acid signaling through regulation of Aldh1a2 expression level. The increased retinoic acid signaling in LSD1-deficient mice suppressed SOX9 expression and impeded the cartilaginous callus formation during fracture repair. The discovery that LSD1 can regulate endochondral ossification during fracture healing will benefit the understanding of bone regeneration and have implications for regenerative medicine.
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