Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Koh, Jae‐Young; Lee, Sook-Jeong

doi:10.1186/s13041-020-00654-w

Cited by 76 publications

(62 citation statements)

References 89 publications

(116 reference statements)

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“…As a member of the MT protein family, MT3 is commonly considered to be expressed in the nervous system [ 32 , 33 ]. It has been shown to have growth inhibitory effect in the brain [ 34 ], with powerful antioxidant capacities [ 35 ]. Our study suggests that MT3 is a novel factor to enhance osteoblast differentiation; MT3 regulates ROS production in this process, and promotes the protein expression of Runx2, Osterix, and Dlx5 in C2C12 cells treated with BMP4.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that beyond the capacity of reducing oxidative stress, MT protein family members have long been considered to be transition metal-binding proteins that can significantly affect metal homeostasis in living organisms [ 53 ]. Although the ability of MT3 to regulate ROS production is closely associated with its metal-binding affinity [ 35 ], indicating experiments about the relationship between MT3 and metal homeostasis in the differentiation process of osteoblasts should be performed in future studies. In addition, as MT1 and MT2 can also affect ROS levels in different organs and tissues [ 54 ], it will be interesting to analyze whether exogenous MT1 or MT2 has the ability to promote osteoblast differentiation in skeletal muscle cells or mesenchymal stromal cells.…”

Section: Discussionmentioning

confidence: 99%

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Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress

Kim

Lee

et al. 2021

IJMS

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Metallothioneins (MTs) are intracellular cysteine-rich proteins, and their expressions are enhanced under stress conditions. MTs are recognized as having the ability to regulate redox balance in living organisms; however, their role in regulating osteoblast differentiation is still unclear. In this research, we found that the expression of MT3, one member of the MT protein family, was specifically upregulated in the differentiation process of C2C12 myoblasts treated with bone morphogenetic protein 4 (BMP4). Transfection with MT3-overexpressing plasmids in C2C12 cells enhanced their differentiation to osteoblasts, together with upregulating the protein expression of bone specific transcription factors runt-related gene 2 (Runx2), Osterix, and distal-less homeobox 5 (Dlx5). Additionally, MT3 knockdown performed the opposite. Further studies revealed that overexpression of MT3 decreased reactive oxygen species (ROS) production in C2C12 cells treated with BMP4, and MT3 silencing enhanced ROS production. Treating C2C12 cells with antioxidant N-acetylcysteine also promoted osteoblast differentiation, and upregulated Runx2/Osterix/Dlx5, while ROS generator antimycin A treatment performed the opposite. Finally, antimycin A treatment inhibited osteoblast differentiation and Runx2/Osterix/Dlx5 expression in MT3-overexpressing C2C12 cells. These findings identify the role of MT3 in osteoblast differentiation and indicate that MT3 may have interesting potential in the field of osteogenesis research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress

Kim

Lee

et al. 2021

IJMS

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“…These observations were confirmed using MT3 knockdown by siRNA in a mouse transformed photoreceptor-cell line (661W) subjected to light-induced damage, observing amplified cell damage and increased production of ROS in response to light exposure [ 283 ]. Altogether, these findings suggested that MT3 might protect more effectively against light-induced retinal damage compared to MT1 and MT2, probably mediated by its antioxidant properties in addition to other major biological roles in cellular processes and diseases [ 287 ].…”

Section: Metallothionein Antioxidant Systemmentioning

confidence: 99%

Antioxidant Defenses in the Human Eye: A Focus on Metallothioneins

et al. 2021

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The human eye, the highly specialized organ of vision, is greatly influenced by oxidants of endogenous and exogenous origin. Oxidative stress affects all structures of the human eye with special emphasis on the ocular surface, the lens, the retina and its retinal pigment epithelium, which are considered natural barriers of antioxidant protection, contributing to the onset and/or progression of eye diseases. These ocular structures contain a complex antioxidant defense system slightly different along the eye depending on cell tissue. In addition to widely studied enzymatic antioxidants, including superoxide dismutase, glutathione peroxidase, catalase, peroxiredoxins and selenoproteins, inter alia, metallothioneins (MTs) are considered antioxidant proteins of growing interest with further cell-mediated functions. This family of cysteine rich and low molecular mass proteins captures and neutralizes free radicals in a redox-dependent mechanism involving zinc binding and release. The state of the art of MTs, including the isoforms classification, the main functions described to date, the Zn-MT redox cycle as antioxidant defense system, and the antioxidant activity of Zn-MTs in the ocular surface, lens, retina and its retinal pigment epithelium, dependent on the number of occupied zinc-binding sites, will be comprehensively reviewed.

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“…It points to a bond between a metal ion and thionein (a cysteine rich apoprotein) rather than describing a function of these kinds of proteins per se , as is the case, for example, with the ADHs discovered a couple of years earlier [ 6 ]. Though it was not immediately obvious what MTs can and cannot do, and what purpose they might serve in a living organism, MTs became the focus of an intense and often controversial corpus of research since the 1960s (e.g., [ 7 , 8 , 9 , 10 , 11 , 12 ]). From a biochemical perspective, there is no question that MTs have unique properties.…”

Section: Introductionmentioning

confidence: 99%

The Enigmatic Metallothioneins: A Case of Upward-Looking Research

Abdin

Jacob

Kästner

2021

IJMS

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In the mid-1950s, Bert Lester Vallee and his colleague Marvin Margoshes discovered a molecule referred to today as metallothionein (MT). Meanwhile, MTs have been shown to be common in many biological organisms. Despite their prevalence, however, it remains unclear to date what exactly MTs do and how they contribute to the biological function of an organism or organ. We investigate why biochemical research has not yet been able to pinpoint the function(s) of MTs. We shall systematically examine both the discovery of and recent research on Dr. Vallee’s beloved family of MT proteins utilizing tools from philosophy of science. Our analysis highlights that Vallee’s initial work exhibited features prototypical of a developing research tradition: it was upward-looking, exploratory, and utilized mere interactions. Since the 1960s, MT research has increasingly become intervention- and hypothesis-based while it remained largely upward-looking in character. Whilst there is no reason to think that upward-looking research cannot successfully yield structure-function mappings, it has not yet been successful in the case of MTs. Thus, we suggest it might be time to change track and consider other research strategies looking into the evolution of MTs. Recent studies in mollusks render research in this direction worthy of pursuit.

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Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Cited by 76 publications

References 89 publications

Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress

Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress

Antioxidant Defenses in the Human Eye: A Focus on Metallothioneins

The Enigmatic Metallothioneins: A Case of Upward-Looking Research

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