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Selenium promotes proliferation of chondrogenic cell ATDC5 by increment of intracellular ATP content under serum deprivation.
"[Low] Selenium (Se) [can result in] chondronecrosis in growth plate and articular cartilage. Se stimulated ATDC5 cell proliferation under serum deprivation but not routine culture. Se promoted G1-phase cell cycle progression along with induction of cyclin D1 expression at the mRNA and protein level{Beta-Catenin increases cyclin D1 and Cyclin D1 increases height up to a point. Cyclin D1 makes cells hypertrophy longer before exiting the cell cycle. If they take too long they just apoptose. So Cyclin D1 works a little like a game of chicken. One key area for future height increase will be determining the optimal level of Cyclin D1 before you get hit by the apoptosis train}. Se increased intracellular ATP content and decreased intracellular superoxide anion concentration without affecting intracellular redox status as estimated by ratio of the reduced and oxidized glutathione. Suppression of intracellular ATP synthesis by glycolysis inhibitor or mitochondrial uncoupler both abrogated Se-mediated cyclin D1 induction{So maybe it's the increase in ATP synthesis that enhances cyclin D1 and not Selenium itself}. Se stimulates proliferation of chondrogenic cell ATDC5 through acceleration of cell cycle progression accompanied with cyclin D1 induction by enhancement of intracellular ATP content."
The question is why Selenium only increased cell proliferation under serum deprivation. A possibility is that Cylin D1 has different effects based on a cells differentiation state. Under a more mature state Cyclin D1 has more an effect on hypertrophy rather than proliferation which could explain the lack of proliferation observed in less serum deprived media. Another explanation is "serum already contains sufficiency trace amounts (about 500 nmol·l–1) of Se"
"[Low] Selenium (Se) [can result in] chondronecrosis in growth plate and articular cartilage. Se stimulated ATDC5 cell proliferation under serum deprivation but not routine culture. Se promoted G1-phase cell cycle progression along with induction of cyclin D1 expression at the mRNA and protein level{Beta-Catenin increases cyclin D1 and Cyclin D1 increases height up to a point. Cyclin D1 makes cells hypertrophy longer before exiting the cell cycle. If they take too long they just apoptose. So Cyclin D1 works a little like a game of chicken. One key area for future height increase will be determining the optimal level of Cyclin D1 before you get hit by the apoptosis train}. Se increased intracellular ATP content and decreased intracellular superoxide anion concentration without affecting intracellular redox status as estimated by ratio of the reduced and oxidized glutathione. Suppression of intracellular ATP synthesis by glycolysis inhibitor or mitochondrial uncoupler both abrogated Se-mediated cyclin D1 induction{So maybe it's the increase in ATP synthesis that enhances cyclin D1 and not Selenium itself}. Se stimulates proliferation of chondrogenic cell ATDC5 through acceleration of cell cycle progression accompanied with cyclin D1 induction by enhancement of intracellular ATP content."
The question is why Selenium only increased cell proliferation under serum deprivation. A possibility is that Cylin D1 has different effects based on a cells differentiation state. Under a more mature state Cyclin D1 has more an effect on hypertrophy rather than proliferation which could explain the lack of proliferation observed in less serum deprived media. Another explanation is "serum already contains sufficiency trace amounts (about 500 nmol·l–1) of Se"
"supplementation of Se significantly decreased G0/G1 phase cell distribution (59·86 ± 0·76% vs 65·09 ± 0·67% of the control group). In contrast, there were no significant change in both S and G2/M phase cell distribution from the cells supplemented with Se versus control. Se promotes cell cycle progression through acceleration of G0/G1 phase. " "Both mRNA and protein expression of cyclin D1 significantly increased at Se concentrations of 25–250 nmol·l–1 for 12-h incubation (increase 1·2, 1·71, 1·62 and 1·5 fold at protein level at concentration of 25, 50, 100 and 250 nmol·l–1 Se, respectively). "<-Note these are both for serum free media. Note cyclin D1 expression increased maximally at 50 nanomol per L.
Now we now that 50 nanomol per L of Selenium maximizes Cyclin D1 but we don't know what levels of Cyclin D1 maximize height growth.
But it's clear that since Selenium stimulated chondrocyte proliferation at 50 nanomol that a 1.71 fold increase in Cyclin D1 is not sufficient for train derailment. But I have no idea how that translates to human doses.
It's possible that the levels of Cyclin D1 needed for train derailment are very high as in the Beta-Catenin study Beta-Catenin never degraded as it was constitutionally active. I was not able to find other studies that show levels of Cyclin D1 necessary to induce apoptosis.
If you want to help growing taller research then researching Cyclin D1 would be a worthwhile use of your time as Cyclin D1 is involved in a number of height increase pathways. The NO and CNP pathway both increase Cyclin D1. FGFR3 decreases Cyclin D1 via Stat1. Inhibiting GSK3-Beta increases Cyclin D1 levels.
It's possible that the levels of Cyclin D1 needed for train derailment are very high as in the Beta-Catenin study Beta-Catenin never degraded as it was constitutionally active. I was not able to find other studies that show levels of Cyclin D1 necessary to induce apoptosis.
If you want to help growing taller research then researching Cyclin D1 would be a worthwhile use of your time as Cyclin D1 is involved in a number of height increase pathways. The NO and CNP pathway both increase Cyclin D1. FGFR3 decreases Cyclin D1 via Stat1. Inhibiting GSK3-Beta increases Cyclin D1 levels.
Effects of selenium and iodine deficiency on bone, cartilage growth plate and chondrocyte differentiation in two generations of rats.
"Sprague-Dawley rats were randomly divided into selenium deficiency (-Se+I), iodine deficiency (+Se-I), combined selenium and iodine deficiency (-Se-I), and selenium and iodine sufficient (+Se+I) groups. Growth of bone and cartilage, and the expression of type X collagen (ColX) and parathyroid hormone-related peptide (PTHrP) were measured in two generations of rats (F(0) and F(1)).
The tibial length in -Se-I rats was significantly shorter in F(1) generation. In +Se-I of F(1) rats, the thickness of the growth plate cartilage, and the proliferative zone was smaller, while in -Se-I rats the growth plate, and the proliferative and hypertrophic zones were also thinner in F(1) generation. In articular cartilage, ColX expression was increased in the deep zone in -Se-I rats of F(0) generation, and in -Se+I, +Se-I and -Se-I rats of F(1) generation. PTHrP expression was increased in the middle zone of -Se+I, +Se-I and -Se-I rats of both F(0) and F(1) generations. In the growth plate cartilage, ColX and PTHrP were expressed in the hypertrophic zone. ColX expression was significantly weaker in -Se+I and -Se-I rats in both F(0) and F(1) generations, while PTHrP expression was stronger in -Se+I, +Se-I and -Se-I rats in both F(0) and F(1) animals."
"There were no significant differences between the groups in F0 rats with respect to tibial length, half frontal plane diameter of tibia, and frontal articular cartilage diameters. However, in F1 rats the tibial length was significantly decreased in −Se−I group"<-surprisingly though in F0 +Selenium +Iodine had the shortest tibial length whereas in F1 +Se+I had the longest Tibial length.
"combined selenium and iodine deficiency only caused a moderate hypothyroidism in rats. It decreased T3 and T4 concentration in F0 and T3 concentration in F1 moderately."
"iodine deficiency starting from the embryo period may retard the chondrocyte differentiation in the growth plate cartilage. Iodine is an essential element of T4 which plays an important role in regulating bone growth and chondrocyte differentiation"
"Spraguee-Dawley rats were randomly divided into selenium deficiency group, iodine deficiency group, combined selenium and iodine deficiency group, and control group.
In articular cartilage, the positive rate of apoptotic chondrocytes stained by TUNEL in the upper and middle zones in selenium deficiency group, iodine deficiency group, and combined selenium and iodine deficiency group were significantly higher than that in control group. The apoptotic chondrocytes were prominent in the middle zone. The positive percentage of chondrocytes apoptosis was not significantly different among these three groups. Compared with the control group, the expressions of both Bcl-2 and Bax were significantly higher in the upper and middle zone in the selenium deficiency group, iodine deficiency group, and combined selenium and iodine deficiency group; however, the expressions of Bcl-2 and Bax were not significantly different among these three groups."
Structural changes in femoral bone tissue of rats after subchronic peroral exposure to selenium.
"Twenty one-month-old male Wistar rats were randomly divided into two experimental groups. In the first group (Se group) young males were exposed to 5 mg Na2SeO3/L in drinking water, for 90 days. Ten one-month-old males without Se administration served as a control group.
The body weight, femoral length[by about 0.2 cm which was approx. a bone length difference of 5%] and cortical bone thickness were significantly decreased in Se group rats. These rats also displayed different microstructure in the middle part of the femur, both in medial and lateral views, where vascular canals expanded into the central area of the bone while, in control rats, these canals occurred only near the endosteal surfaces. Additionally, a smaller number of primary and secondary osteons was identified in Se group rats. Histomorphometric analyses revealed significant increases for area, perimeter, maximum and minimum diameters of primary osteons' vascular canals but significant reductions for all measured variables of Haversian canals and secondary osteons."
Selenium may result in decreased secretion of growth hormone (GH) and somatomedin C
Selenium effect on selenoprotein transcriptome in chondrocytes.
"Selenium is an essential micronutrient and exerts its biological functions predominantly through selenoproteins. Selenium deficiency is associated with cartilage function. This study demonstrated that all 24 selenoprotein transcripts in mouse genome were detectable in ATDC5 chondrocytes except deiodinase 1 (DIO1), DIO2, and selenoprotein V (Sel V), while all 25 selenoprotein{LSJL downregulates D5Wsu178e which encodes for a selenoprotein} transcripts in human genome were detectable in C28/I2 chondrocytes except glutathione peroxidase 6 (GPx6) and DIO1. In addition, gene expression of five selenoproteins (GPx1, Sel H, Sel N, Sel P, and Sel W) was up-regulated and two selenoproteins (SPS2 and Sel O) was down-regulated by sodium selenite (Se) in both ATDC5 and C28/I2 cells. Gene expression of six selenoproteins (TrxR1, Sel I, Sel M, Sel R, Sel S, Sel T) and one selenoprotein (GPx3) was up-regulated by Se in ATDC5 and C28/I2 cells, respectively. Gene expression of one selenoprotein (TrxR2) was down-regulated by Se only in ATDC5 cells. Further transcription inhibition assay showed that both transcriptional and posttranscriptional mechanisms involved in Se-regulated gene expression of GPx1, TrxR1, TrxR2, SPS2, Sel O, and Sel S. However, Se-regulated gene expression of Sel H, Sel I, Sel M, Sel N, Sel P, Sel R, Sel T, and Sel W mainly at posttranscriptional level. Moreover, new protein synthesis inhibition assay indicated that Se-mediated new protein synthesis also played roles in Se-regulated gene expression of GPx1, TrxR1, TrxR2, Sel H, Sel O, Sel P, Sel R, and Sel W."
LSJL also downregulates Selenium binding related gene Sephs1 and Hrpll.
"In mammals, the incorporation of Sec into selenoproteins occurs via a stop codon UGA and requires recoding by means of a Sec-insertion sequence (SECIS) with a specific selenocysteyl-tRNA (tRNA-Sec) and a number of trans-acting proteins, including the SECIS binding protein 2 (SBP2), the specialized translation elongation factor EFSec, ribosomal protein L30, and others"
" C-28/I2 cells express high levels of matrix-anabolic and matrix-catabolic genes and thus are suitable for investigation of chondrocyte anabolic and catabolic activity"
The key is if any of these seleproteins affect height.
Structural changes in femoral bone tissue of rats after subchronic peroral exposure to selenium.
"Twenty one-month-old male Wistar rats were randomly divided into two experimental groups. In the first group (Se group) young males were exposed to 5 mg Na2SeO3/L in drinking water, for 90 days. Ten one-month-old males without Se administration served as a control group.
The body weight, femoral length[by about 0.2 cm which was approx. a bone length difference of 5%] and cortical bone thickness were significantly decreased in Se group rats. These rats also displayed different microstructure in the middle part of the femur, both in medial and lateral views, where vascular canals expanded into the central area of the bone while, in control rats, these canals occurred only near the endosteal surfaces. Additionally, a smaller number of primary and secondary osteons was identified in Se group rats. Histomorphometric analyses revealed significant increases for area, perimeter, maximum and minimum diameters of primary osteons' vascular canals but significant reductions for all measured variables of Haversian canals and secondary osteons."
Selenium may result in decreased secretion of growth hormone (GH) and somatomedin C
Selenium effect on selenoprotein transcriptome in chondrocytes.
"Selenium is an essential micronutrient and exerts its biological functions predominantly through selenoproteins. Selenium deficiency is associated with cartilage function. This study demonstrated that all 24 selenoprotein transcripts in mouse genome were detectable in ATDC5 chondrocytes except deiodinase 1 (DIO1), DIO2, and selenoprotein V (Sel V), while all 25 selenoprotein{LSJL downregulates D5Wsu178e which encodes for a selenoprotein} transcripts in human genome were detectable in C28/I2 chondrocytes except glutathione peroxidase 6 (GPx6) and DIO1. In addition, gene expression of five selenoproteins (GPx1, Sel H, Sel N, Sel P, and Sel W) was up-regulated and two selenoproteins (SPS2 and Sel O) was down-regulated by sodium selenite (Se) in both ATDC5 and C28/I2 cells. Gene expression of six selenoproteins (TrxR1, Sel I, Sel M, Sel R, Sel S, Sel T) and one selenoprotein (GPx3) was up-regulated by Se in ATDC5 and C28/I2 cells, respectively. Gene expression of one selenoprotein (TrxR2) was down-regulated by Se only in ATDC5 cells. Further transcription inhibition assay showed that both transcriptional and posttranscriptional mechanisms involved in Se-regulated gene expression of GPx1, TrxR1, TrxR2, SPS2, Sel O, and Sel S. However, Se-regulated gene expression of Sel H, Sel I, Sel M, Sel N, Sel P, Sel R, Sel T, and Sel W mainly at posttranscriptional level. Moreover, new protein synthesis inhibition assay indicated that Se-mediated new protein synthesis also played roles in Se-regulated gene expression of GPx1, TrxR1, TrxR2, Sel H, Sel O, Sel P, Sel R, and Sel W."
LSJL also downregulates Selenium binding related gene Sephs1 and Hrpll.
"In mammals, the incorporation of Sec into selenoproteins occurs via a stop codon UGA and requires recoding by means of a Sec-insertion sequence (SECIS) with a specific selenocysteyl-tRNA (tRNA-Sec) and a number of trans-acting proteins, including the SECIS binding protein 2 (SBP2), the specialized translation elongation factor EFSec, ribosomal protein L30, and others"
" C-28/I2 cells express high levels of matrix-anabolic and matrix-catabolic genes and thus are suitable for investigation of chondrocyte anabolic and catabolic activity"
The key is if any of these seleproteins affect height.
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