Zinc Homeostasis in Bone: Zinc Transporters and Bone Diseases

Zinc is an essential micronutrient that plays critical roles in numerous physiological processes, including bone homeostasis. The majority of zinc in the human body is stored in bone. Zinc is not only a component of bone but also an essential cofactor of many proteins involved in microstructural stability and bone remodeling. There are two types of membrane zinc transporter proteins identified in mammals: the Zrt- and Irt-like protein (ZIP) family and the zinc transporter (ZnT) family. They regulate the influx and efflux of zinc, accounting for the transport of zinc through cellular and intracellular membranes to maintain zinc homeostasis in the cytoplasm and in intracellular compartments, respectively. Abnormal function of certain zinc transporters is associated with an imbalance of bone homeostasis, which may contribute to human bone diseases. Here, we summarize the regulatory roles of zinc transporters in different cell types and the mechanisms underlying related pathological changes involved in bone diseases. We also present perspectives for further studies on bone homeostasis-regulating zinc transporters.

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Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells

Journal of Immunology Research ◽

10.1155/2018/9365747 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Bum-Ho Bin ◽

Juyeon Seo ◽

Sung Tae Kim

Keyword(s):

Immune Cells ◽

Drug Targets ◽

Therapeutic Potential ◽

Family Members ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Function Structure ◽

Rich Domain ◽

Zip Family

Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses. Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. There are 14 ZIP family members in humans. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology; it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Ten family members have been identified. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential.

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Zinc Transporter ZIP12 Maintains Zinc Homeostasis and Protects Spermatogonia From Oxidative Stress During Spermatogenesis

10.21203/rs.3.rs-800872/v1 ◽

2021 ◽

Author(s):

Xinye Zhu ◽

Chengxuan Yu ◽

Wangshu Wu ◽

Lei Shi ◽

Chenyi Jiang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Male Fertility ◽

Sperm Quality ◽

Zinc Level ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Mouse Testis ◽

Zinc Transporters ◽

Wide Range

Abstract Background: Overwhelming evidences now suggest oxidative stress is a major cause of sperm dysfunction and male infertility. Zinc is an important non-enzyme antioxidant with a wide range of biological functions and plays a significant role in preserving male fertility. Notably, zinc trafficking through the cellular and intracellular membrane is endorsed by precise families of zinc transporters, i.e. SLC39s/ZIPs and SLC30s/ZnTs. However, the expression and function of zinc transporters in the male germ cells were rarely reported. The aim of this study is to determine the crucial zinc transporter responsible for the maintenance of spermatogenesis.Methods: In the present study, we investigated the expression of all fourteen ZIP members in mouse testis and further analyzed the characteristic of ZIP12 expression in testis and spermatozoa by qRT-PCR, immunoblot and immunohistochemistry analyses. To explore the antioxidant role of ZIP12 in spermatogenesis, an obese mouse model fed with high-fat-diet was employed to confirm the correlation between ZIP12 expression level and sperm quality. Furthermore, ZIP12 expression in response to oxidative stress in a spermatogonia cell line, C18-4 cells, was determined and its function involved in regulating cell viability and apoptosis was investigated by RNAi experiment. Results: We initially found that ZIP12 expression in mouse testis was significantly high compared to other members of ZIPs and its mRNA and protein were intensively expressed in testis rather than the other tissues. Importantly, ZIP12 was intensively abundant in spermatogonia and spermatozoa, both in mice and humans. Moreover, ZIP12 expression in testis significantly decreased in obese mice, which associated with reduced sperm zinc content, excessive sperm ROS, poor sperm quality and male subfertility. Similarly, its expression in C18-4 cells significantly declined in response to oxidative stress. Additionally, reduced ZIP12 expression by RNAi associated with a decline in zinc level subsequently caused low cell viability and high cell apoptosis in C18-4 cells. Conclusions: The zinc transporter ZIP12 is intensively expressed in testis, especially in spermatogonia and spermatozoa. ZIP12 may play a key role in maintaining intracellular zinc level in spermatogonia and spermatozoa, by which it resists oxidative stress during spermatogenesis and therefore preserves male fertility.

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Zinc, metallothioneins and immunosenescence

Proceedings of The Nutrition Society ◽

10.1017/s0029665110001862 ◽

2010 ◽

Vol 69 (3) ◽

pp. 290-299 ◽

Cited By ~ 22

Author(s):

E. Mocchegiani ◽

M. Malavolta ◽

L. Costarelli ◽

R. Giacconi ◽

C. Cipriano ◽

...

Keyword(s):

Innate Immunity ◽

Zinc Supplementation ◽

Killer Cell ◽

Zinc Content ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Intracellular Zinc ◽

Natural Killer Cell Cytotoxicity ◽

Zip Family

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of ‘second messenger’. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C–carriers) in the IL-6–174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C+carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C–carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6−174G/C locus when associated with those of the MT1A+647A/C locus are useful tools for the choice of old people for zinc supplementation.

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The Effects of Short-Term Zinc Feeding on Zinc Absorption and Zinc Transporter Expression in the Small Intestine of Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_054 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1827-1827

Author(s):

Cassandra Olson ◽

Alyssa Kelley ◽

James McClung ◽

Stephen Hennigar

Keyword(s):

Small Intestine ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Zinc Absorption ◽

Intestinal Segment ◽

Deficient Diet ◽

Us Government ◽

Zinc Deficient Diet ◽

Transporter Expression

Abstract Objectives Zinc homeostasis is primarily maintained by zinc transporters that regulate zinc uptake and efflux in the small intestine; however, no study to date has comprehensively examined zinc transporter expression in the small intestine of mice fed varying levels of dietary zinc. The objective of this study was to determine the effects of zinc absorption and zinc transporter expression in the small intestine of mice fed varying levels of zinc for one week. Methods Seven-week-old male C57BL/6 J mice were randomized to either a standard AIN-93 G diet containing 30 ppm zinc (zinc adequate) or modified AIN-93 G diets containing <1 ppm (zinc deficient) or 100 ppm zinc (zinc supplemented) for one week (n = 5–10/diet). Mice were given an oral gavage containing a slurry of zinc deficient feed and 10 μg 67 Zn; plasma isotope appearance was determined 6-h later by ICP-MS. Gene expression of Slc39a1–14 and Slc30a1–10 was determined in each intestinal segment (duodenum, jejunum, and ileum) by RT-qPCR. Results Plasma and liver zinc concentrations were not different after one week of feeding (P > 0.05 for both). Plasma appearance of 67 Zn was greater in mice fed the zinc deficient (mean ± SD: 0.36 ± 0.03 ng/mL) compared to the zinc adequate (0.22 ± 0.03 ng/mL) and zinc supplemented (0.22 ± 0.03 ng/mL, P < 0.0001 for both) diets. With the exception of Slc39a12, Slc30a3, and Slc30a8, the remaining zinc transporters were expressed across all diets and intestinal segments. Expression of Slc39a1, Slc39a4, Slc39a5, Slc39a7, Slc39a9, Slc39a11, Slc39a14, Slc30a2, Slc30a4, Slc30a5, Slc30a6, and Slc30a9 changed with diet (Pdiet < 0.05 for all); expression of Slc39a3, Slc39a7, Slc39a9 and Slc30a5 changed by intestinal segment (Psegment < 0.05 for all). Of those transporters expressed, Slc39a4 was positively associated with plasma appearance of 67 Zn (r = 0.645, P < 0.0001) and increased 7-fold in mice consuming the zinc deficient diet compared to the zinc adequate and zinc supplemented diets (P < 0.0001 for both). Conclusions Although most zinc transporters are expressed in the small intestine and likely function in concert, fluctuations in fractional zinc absorption are positively correlated with Slc39a4 expression in the small intestine. Funding Sources The views expressed herein are those of the authors and do not reflect official policy of the Army, DoD, or US Government. Supported by MRDC.

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The role of zinc transporter proteins as predictive and prognostic biomarkers of hepatocellular cancer

PeerJ ◽

10.7717/peerj.12314 ◽

2021 ◽

Vol 9 ◽

pp. e12314

Author(s):

Ceylan V. Bitirim

Keyword(s):

Tumor Progression ◽

Zinc Deficiency ◽

Zinc Level ◽

Zinc Transporter ◽

Tumor Formation ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Transporter Proteins ◽

Grade Ii ◽

Cellular Zinc

Identification of the key processes involved in the tumor progression, malignancy and the molecular factors which are responsible for the transition of the cirrhotic cells to the tumor cells, contribute to the detection of biomarkers for diagnosis of hepatocellular carcinoma (HCC) at an early stage. According to clinical data, HCC is mostly characterized by a significant decrease in zinc levels. It is strongly implied that zinc deficiency is the major event required in the early stages of tumor formation and development of malignancy. Due to this reason, the definition of the molecular players which have a role in zinc homeostasis and cellular zinc level could give us a clue about the transition state of the cirrhosis to hepatic tumor formation. Despite the well-known implications of zinc in the development of HCCthe correlation of the expression of zinc transporter proteins with tumor progression and malignancy remain largely unknown. In the present study, we evaluated in detail the relationship of zinc deficiency on the prognosis of early HCC patients. In this study, we aimed to test the potential zinc transporters which contribute tothe transformation of cirrhosis to HCCand the progression of HCC. Among the 24 zinc transporter proteins, the proteins to be examined were chosen by using Gene Expression Profiling Interactive Analysis (GEPIA) webpage and RNA-seq analysis using TCGA database. ZIP14 and ZIP5 transporters were found as common differentially expressed genes from both bioinformatic analyses. ZnT1, ZnT7 and ZIP7 transporters have been associated with tumor progression. Relative abundance of ZnT1, ZIP5 and ZIP14 protein level was determined by immunohistochemistry (IHC) in surgically resected liver specimens from 16 HCC patients at different stages. IHC staining intensity was analyzed by using ImageJ software and scored with the histological scoring (H-score) method. The staining of ZnT1 was significantly higher in Grade III comparing to Grade II and Grade I. On the contrary, ZIP14 staining decreased almost 10-foldcomparing to Grade Iand Grade II. ZIP5 staining was detected almost 2-fold higher in cirrhosis than HCC. But ZnT1 staining was observed almost 3-fold lower in cirrhosis comparing to HCC. Intracellular free zinc level was measured by flow cytometry in Hep40 and Snu398 cells using FluoZin-3 dye. The intracellular free zinc level was almost 9-fold decreased in poor differentiated Snu398 HCC cells comparing to well differentiated Hep40 HCC cells.This report establishes for the first time the correlation between the expression pattern of ZIP14, ZnT1 and ZIP5 and significant zinc deficiency which occurs concurrently with the advancing of malignancy. Our results provide new molecular insight into ZnT1, ZIP14 and ZIP5 mediated regulation of cellular zinc homeostasis and indicate that zinc transporters might be important factors and events in HCC malignancy, which can lead to the development of early biomarkers.

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Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

Frontiers in Endocrinology ◽

10.3389/fendo.2021.815386 ◽

2022 ◽

Vol 12 ◽

Author(s):

Sooyeon Lee ◽

Benjamin Thilo Krüger ◽

Anita Ignatius ◽

Jan Tuckermann

Keyword(s):

Circadian Rhythm ◽

Adverse Effects ◽

Bone Cells ◽

Inflammatory Diseases ◽

Common Adverse Effect ◽

Cell Types ◽

Bone Diseases ◽

Term Therapy ◽

Bone Homeostasis ◽

Long Term Therapy

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

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The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Physiological Reviews ◽

10.1152/physrev.00035.2014 ◽

2015 ◽

Vol 95 (3) ◽

pp. 749-784 ◽

Cited By ~ 305

Author(s):

Taiho Kambe ◽

Tokuji Tsuji ◽

Ayako Hashimoto ◽

Naoya Itsumura

Keyword(s):

Zinc Transporter ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Whole Body ◽

Biological Processes ◽

Transport Mechanisms ◽

Intercellular Signaling ◽

Zip Transporters ◽

Related Proteins ◽

Made In

Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

Stresses ◽

10.3390/stresses1020007 ◽

2021 ◽

Vol 1 (2) ◽

pp. 78-89

Author(s):

Soisungwan Satarug ◽

Scott H. Garrett ◽

Seema Somji ◽

Mary Ann Sens ◽

Donald A. Sens

Keyword(s):

Mammalian Cells ◽

Defense Mechanisms ◽

Prolonged Exposure ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Aberrant Expression ◽

Metal Transporters ◽

Zip Family ◽

Cation Diffusion Facilitators ◽

Cellular Zinc

Maintenance of zinc homeostasis is pivotal to the regulation of cell growth, differentiation, apoptosis, and defense mechanisms. In mammalian cells, control of cellular zinc homeostasis is through zinc uptake, zinc secretion, and zinc compartmentalization, mediated by metal transporters of the Zrt-/Irt-like protein (ZIP) family and the Cation Diffusion Facilitators (CDF) or ZnT family. We quantified transcript levels of ZIP and ZnT zinc transporters expressed by non-tumorigenic UROtsa cells and compared with those expressed by UROtsa clones that were experimentally transformed to cancer cells by prolonged exposure to cadmium (Cd). Although expression of the ZIP8 gene in parent UROtsa cells was lower than ZIP14 (0.1 vs. 83 transcripts per 1000 β-actin transcripts), an increased expression of ZIP8 concurrent with a reduction in expression of one or two zinc influx transporters, namely ZIP1, ZIP2, and ZIP3, were seen in six out of seven transformed UROtsa clones. Aberrant expression of the Golgi zinc transporters ZIP7, ZnT5, ZnT6, and ZnT7 were also observed. One transformed clone showed distinctively increased expression of ZIP6, ZIP10, ZIP14, and ZnT1, with a diminished ZIP8 expression. These data suggest intracellular zinc dysregulation and aberrant zinc homeostasis both in the cytosol and in the Golgi in the transformed UROtsa clones. These results provide evidence for zinc dysregulation in transformed UROtsa cells that may contribute in part to their malignancy and/or muscle invasiveness.

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Lactoferrin in Bone Tissue Regeneration

Current Medicinal Chemistry ◽

10.2174/0929867326666190503121546 ◽

2020 ◽

Vol 27 (6) ◽

pp. 838-853 ◽

Cited By ~ 6

Author(s):

Madalina Icriverzi ◽

Valentina Dinca ◽

Magdalena Moisei ◽

Robert W. Evans ◽

Mihaela Trif ◽

...

Keyword(s):

Bone Tissue ◽

Tissue Regeneration ◽

Bone Cells ◽

Bone Diseases ◽

Biologically Active Compounds ◽

Biologically Active ◽

Bone Tissue Regeneration ◽

Bone Homeostasis ◽

Active Compounds

: Among the multiple properties exhibited by lactoferrin (Lf), its involvement in bone regeneration processes is of great interest at the present time. A series of in vitro and in vivo studies have revealed the ability of Lf to promote survival, proliferation and differentiation of osteoblast cells and to inhibit bone resorption mediated by osteoclasts. Although the mechanism underlying the action of Lf in bone cells is still not fully elucidated, it has been shown that its mode of action leading to the survival of osteoblasts is complemented by its mitogenic effect. Activation of several signalling pathways and gene expression, in an LRPdependent or independent manner, has been identified. Unlike the effects on osteoblasts, the action on osteoclasts is different, with Lf leading to a total arrest of osteoclastogenesis. : Due to the positive effect of Lf on osteoblasts, the potential use of Lf alone or in combination with different biologically active compounds in bone tissue regeneration and the treatment of bone diseases is of great interest. Since the bioavailability of Lf in vivo is poor, a nanotechnology- based strategy to improve the biological properties of Lf was developed. The investigated formulations include incorporation of Lf into collagen membranes, gelatin hydrogel, liposomes, loading onto nanofibers, porous microspheres, or coating onto silica/titan based implants. Lf has also been coupled with other biologically active compounds such as biomimetic hydroxyapatite, in order to improve the efficacy of biomaterials used in the regulation of bone homeostasis. : This review aims to provide an up-to-date review of research on the involvement of Lf in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration.

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Calcium and Vitamin D Supplementation. Myths and Realities with Regard to Cardiovascular Risk

Current Vascular Pharmacology ◽

10.2174/1570161117666190408165805 ◽

2019 ◽

Vol 17 (6) ◽

pp. 610-617 ◽

Cited By ~ 10

Author(s):

Giovanna Muscogiuri ◽

Luigi Barrea ◽

Barbara Altieri ◽

Carolina Di Somma ◽

Harjit pal Bhattoa ◽

...

Keyword(s):

Vitamin D ◽

Side Effects ◽

Secondary Hyperparathyroidism ◽

Calcium Supplementation ◽

Physiological Role ◽

Bone Diseases ◽

Current Evidence ◽

Bone Homeostasis ◽

Mineral Density ◽

Muscle Health

Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.

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