Zinc, a metal found in the Earth's crust, is indispensable for human health. In the human body, around 60% of zinc is present in muscles, 30% in bones, and the remaining 10% in skin, hair, pancreas, ...kidneys and plasma. An adequate zinc balance is essential for the maintenance of skeletal growth, development and function. It is also necessary for basic cellular functions including enzyme activation, cell signaling and energy metabolism. Inadequate zinc status is associated with a wide variety of systemic disorders including cardiovascular impairment, musculoskeletal dysfunctions and oromaxillary diseases. In this article, we briefly discuss the role of zinc deficiency in the genesis of various oromaxillary diseases, and explain why adequate zinc homeostasis is vital for the maintenance of oral and general health.
Studies have shown that mesenchymal stem/stromal cells (MSCs) from bone marrow are involved in the growth and metastasis of solid tumors but the mechanism remains unclear in osteosarcoma (OS). ...Previous studies have raised the possibility that OS cells may receive support from associated MSCs in the nutrient deprived core of the tumors through the release of supportive macromolecules and growth factors either in vesicular or non-vesicular forms. In the present study, we used stressed mesenchymal stem cells (SD-MSCs), control MSCs and OS cells to examine the hypothesis that tumor-associated MSCs in nutrient deprived core provide pro-proliferative, anti-apoptotic, and metastatic support to nearby tumor cells. Assays to study of the effects of SD-MSC conditioned media revealed that OS cells maintained proliferation when compared to OS cells grown under serum-starved conditions alone. Furthermore, OS cells in MSCs and SD-MSC conditioned media were significantly resistant to apoptosis and an increased wound healing rate was observed in cells exposed to either conditioned media or EVs from MSCs and SD-MSCs. RT-PCR assays of OS cells incubated with extracellular vesicles (EVs) from SD-MSCs revealed microRNAs that could potentially target metabolism and metastasis associated genes as predicted by in silico algorithms, including monocarboxylate transporters, bone morphogenic receptor type 2, fibroblast growth factor 7, matrix metalloproteinase-1, and focal adhesion kinase-1. Changes in the expression levels of focal adhesion kinase, STK11 were confirmed by quantitative PCR assays. Together, these data indicate a tumor supportive role of MSCs in osteosarcoma growth that is strongly associated with the miRNA content of the EVs released from MSCs under conditions that mimic the nutrient deprived core of solid tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Muscle cachexia is a catabolic response, usually takes place in various fatal diseases, such as sepsis, burn injury, and chronic kidney disease. Muscle cachexia is also a common co-morbidity seen in ...the vast majority of advanced cancer patients, often associated with low quality of life and death due to general organ dysfunction. The triggering events and underlying molecular mechanisms of muscle wasting are not yet clearly defined. Our recent study has shown that the ectopic expression of Twist1 in muscle progenitor cells is sufficient to drive muscle structural protein breakdown and attendant muscle atrophy, reminiscent of muscle cachexia. Intriguingly, muscle Twist1 expression is highly induced in cachectic muscles from several mouse models of pancreatic ductal adenocarcinoma (PDAC), raising the interesting possibility that Twist1 may mediate PDAC-driven muscle cachexia. Along these lines, both genetic and pharmacological inactivation of Twist1 function was highly significant at protecting against cancer cachexia, which translated into a significant survival benefit in the experimental PDAC animals. From a translational perspective, elevated expression of Twist1 is also detected in cancer patients with severe muscle wasting, implicating a role of Twist1 in cancer cachexia, and further providing a possible target for therapeutic attenuation of cachexia to improve cancer patient survival. In this article, we will briefly summarize how Twist1 acts as a master regulator of tumor-induced cachexia, and discuss the relevance of our findings to muscle wasting diseases in general. The mechanism of decreased muscle mass in various catabolic conditions is thought to rely on similar pathways, and, therefore, Twist1-induced cancer cachexia may benefit diverse groups of patients with clinical complications associated with loss of muscle mass and functions, beyond the expected benefits for cancer patients.
TG-interacting factor 1 (TGIF1) exerts inhibitory effects on transforming growth factor-beta (TGF-β) signaling by suppressing Smad signaling pathway at multiple levels. TGIF1 activity is important ...for normal embryogenesis and organogenesis, yet its dysregulation can culminate in tumorigenesis. For instance, increased expression of TGIF1 correlates with poor prognosis in triple-negative breast cancer patients, and enforced expression of TGIF1 facilitates Wnt-driven mammary tumorigenesis, suggesting that TGIF1 might function as an oncoprotein. Quite surprisingly, TGIF1 has recently been shown to function as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC), possibly owing to its ability to antagonize the pro-malignant transcription factor Twist1. In this article, we will briefly elaborate on the biological and clinical significance of the unique tumor-suppressive function of TGIF1 and its functional interaction with Twist1 in the context of PDAC pathogenesis and progression.
Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 ...(Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2⁺/⁻ mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.
Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for ...peroxi‐some proliferator‐activated receptor‐γ (PPAR‐γ), a master regulator of adipocyte differentiation, and an adipo‐genesis‐promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho‐knockout mice (11.7±0.3 g at 9 wk), leptin‐deficient (ob/ob) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity ob/ob‐klotho double‐knockout (DKO) mice. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild‐type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob‐klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob‐klotho DKO mice had significantly (P<0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob‐klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob‐klotho DKO mice, compared to their ob/ob counterparts (ob/ob vs. ob/ob‐klotho DKO: 266 ± 36 vs. 65 ±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high‐fat‐diet‐induced obesity, we provided a high‐fat (60%) diet to klotho‐knockout mice and compared them with normal‐fat (20%) diet‐fed klotho‐knockout mice. No significant difference in body weight was detected in klotho‐knockout mice fed either the normal‐fat diet or high‐fat diet, while WT mice fed the high‐fat diet gradually gained body weight, compared to the normal‐fat‐diet‐fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications.—Ohnishi, M., Kato, S., Akiyoshi, J., Atfi, A., Razzaque, M. S., Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions. FASEB J. 25, 2031–2039 (2011). www.fasebj.org
In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during ...longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP−/− and chondrocyte-specific PTHR1−/− mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.
► zfp521 is a PTHrP target gene and effector in growth plate chondrocytes ► Zfp521 antagonizes Runx2 in a HDAC4-mediated manner ► Zfp521 controls chondrocyte proliferation, hypertrophy, and survival
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