Journal of Cellular Physiology最新文献

Osteoclasts are bone-resorbing cells, and understanding the pathways involved in osteoclast differentiation and activation is essential for developing treatments for bone diseases such as osteoporosis. Since osteoclast differentiation is regulated by signaling pathways such as Akt, MAPK, and NF-κB, it is important to identify their regulators. Makorin ring finger protein 1 (MKRN1), a conserved member of the ring finger protein family, is closely linked to the regulation of Akt and AMP-activated protein kinase (AMPK), important signaling pathways in osteoclastogenesis. However, its specific role in osteoclasts has not been revealed. Mkrn1 was overexpressed using a retrovirus or silenced using small interfering RNA (siRNA) in bone marrow-derived macrophages (BMMs). Subsequently, osteoclast differentiation was induced using receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and assessed via tartrate-resistant acid phosphatase (TRAP) staining. Additionally, the role of Mkrn1 in osteoclastogenesis was confirmed using Mkrn1-deficient cells. Western blot analysis was employed to evaluate Mkrn1-associated Akt and AMPK activation. The bone phenotype of Mkrn1-deficient mice was investigated through bone analysis. This study revealed that Mkrn1 significantly influences RANKL-induced osteoclastogenesis. Overexpression of Mkrn1 in BMMs enhanced osteoclast differentiation by promoting Akt phosphorylation and inhibiting AMPK phosphorylation upon RANKL stimulation. Conversely, siRNA-mediated downregulation of MKRN1 reduced Akt phosphorylation and increased AMPK phosphorylation, impairing osteoclastogenesis. Furthermore, in vivo studies using Mkrn1 knockout mice revealed a phenotype with increased bone volume. Our findings establish Mkrn1 as a positive regulator of osteoclast differentiation, highlighting its potential as a therapeutic target for bone diseases characterized by excessive bone resorption.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with limited cardiac regeneration hindering recovery in damaged hearts. We previously demonstrated that T-box transcription factor 20 (Tbx20) and bone morphogenetic protein 2 (Bmp2) are crucial for cardiac homeostasis by promoting cardiomyocyte proliferation following endoplasmic reticulum (ER) stress. Here we showed that various stressors (ER stress, diabetes, type2 myocardial infarction, high-fat diet) over shorter and longer durations in vivo lead to distinct expression patterns of Tbx20 and Bmp2 in cardiomyocytes and fibroblasts. In vitro, stress induction resulted in similar expression patterns of Tbx20 and Bmp2, initially increasing in H9c2 cardiomyocytes before showing a sharp decline. In contrast, Bmp2 significantly increased in primary rat adult cardiac fibroblasts during increasing stress. MicroRNAs (miRNAs) are pleiotropic regulators of cardiac development and disease, and are promising therapeutic interventions for regulating cardiac regeneration. Upon delineating the cause of the differential regulation, in silico analysis revealed the presence of putative miR-101-3p binding site in the 3'UTR of tbx20 and Bmp2 inhibitor noggin (nog) gene, which was corroborated by dual-luciferase reporter assay. The expression of miR-101-3p was elevated upon prolonged stress across all the cardiac injury models. In vitro, increasing stress resulted in increased expression of miR-101-3p. MiR-101-3p agonist suppressed and antagonist elevated the expression of Tbx20 in H9c2 cardiomyocytes. Ectopic overexpression of miR-101-3p or siRNA-mediated knockdown of Tbx20 in H9c2 cardiomyocytes heightened the expression of senescence markers (p21, p16, γH₂AX). Furthermore, miR-101-3p targeted Nog under stress, indirectly raising Bmp2 and inflammatory response (TNF-α and IL6) in primary cardiac fibroblasts, thereby exacerbating cardiomyopathy. Inhibition of miR-101-3p reversed its inhibitory effect on Tbx20 and Nog. This study uncovers a novel regulatory mechanism where miR-101-3p acts as a repressor of cardiac genes to induce cardiac senescence and inflammation, positioning miR-101-3p as a therapeutic target for cardiomyopathy.

The tetratricopeptide repeat domain 7 (TTC7) family, comprising the paralogs TTC7A and TTC7B, encodes scaffold proteins that are critical for membrane signaling and cellular homeostasis. Although mutations in TTC7 family have been implicated in immune and developmental disorders, their roles in cancer, particularly head and neck cancer (HNC), remain largely unexplored. In this study, we systematically analyzed the expression, prognostic relevance, and biological functions of TTC7B in HNC using transcriptomic data, immunohistochemistry on tissue microarrays, in vitro functional assays, and integrative bioinformatic approaches. Compared with TTC7A, TTC7B was markedly upregulated in HNC and associated with poor survival. In vitro assays confirmed that TTC7B promotes HNC cell migration and invasion. Among the potential co-dependent molecules, JNK1-associated membrane protein (JKAMP) emerged as a significantly co-expressed transcript, with TTC7B^high/JKAMP^high patients consistently exhibiting the poorest survival rates. Mechanistically, TTC7B activated AKT to upregulate JKAMP, thereby enhancing malignant phenotypes. Pharmacological inhibition of AKT abolished TTC7B-induced phosphorylation of AKT and JKAMP expression, suppressing migration and invasion, whereas IGF-1–mediated AKT activation restored JKAMP expression and rescued TTC7B-knockdown phenotypes. Moreover, JKAMP silencing in TTC7B-overexpressing cells markedly reduced migration and invasion, indicating the oncogenic TTC7B–AKT–JKAMP signaling axis. In parallel, miR-183-5p suppressed TTC7B–AKT–JKAMP signaling, suggesting a potential regulatory mechanism. High TTC7B expression also attenuated the survival advantage conferred by tumor-infiltrating CD8⁺ T cells, suggesting that TTC7B may promote immunosuppressive tumor microenvironment. Collectively, our findings establish TTC7B as a novel oncogenic factor in HNC that promotes tumor progression through the TTC7B–AKT–JKAMP axis and immune modulation, highlighting its potential as a prognostic biomarker and therapeutic target for HNC.

Growing evidence has established the imprinted gene neuronatin (NNAT) as a key regulator in human metabolic disorders, particularly obesity and type 2 diabetes. Its expression is prominently detected in major neuroendocrine and metabolic tissues, including the hypothalamus, pancreas, adipose tissue, and skeletal muscle. NNAT orchestrates diverse cellular processes through its regulation of intracellular calcium dynamics and pathological insulin secretion. Notably, NNAT exhibits nutrient-responsive regulation and is a crucial modulator of glucose homeostasis, adaptive thermogenesis, and overall energy balance. These pleiotropic functions position NNAT as an attractive therapeutic target for obesity-related metabolic disorders. This comprehensive review systematically evaluates the multifaceted roles of NNAT in metabolic regulation, with a particular focus on its tissue-specific mechanisms in both physiological and pathological states while integrating the current understanding of its contributions to systemic metabolic homeostasis.

Research in the past decade has elucidated the explicit role of the immune system in the pathophysiology of osteoporosis. Recent studies have further unraveled the complex interactions between bone and immune cells and explored safe, effective immunomodulatory approaches—such as probiotics—for preventing and managing osteoporosis. As a result, various immune factors have continuously been discovered to play specific roles in maintaining bone homeostasis. The role of Tregs in the context of postmenopausal osteoporosis (PMO) is already well established. While Foxp3⁺ Tregs are mostly matured in the thymus (tTregs), some are also produced from Foxp3⁻CD4⁺ T-cell precursors in the peripheral tissues (i.e., pTregs). Notably, the specific role of pTregs and tTregs in PMO remains to be elucidated. Here, we reveal that estrogen-deficient inflammatory conditions in PMO disrupt the balance of tTregs and pTregs. Interestingly, within pTregs, the population of RORγT⁻ pTregs and RORγT⁺ pTregs is further altered, along with simultaneous expansion of Th17 cells—likely through the conversion of RORγT⁻ pTregs into Th17 cells. Notably, supplementation with Lactobacillus acidophilus (LA) restores the homeostasis of RORγT⁻ pTregs and Th17 cells in a butyrate-mediated manner. Moreover, it was observed that butyrate-primed RORγT⁻ pTregs have reduced osteoclastogenic potential. Collectively, our findings for the first time reveal the pivotal role of gut resident RORγT⁻ pTregs–Th17 cell axis in the pathophysiology of PMO.