Wednesday, November 10, 2010

Can Zinc make me taller?

Zinc is a mineral that is often taken by bodybuilders as part of ZMA.  The similarities between muscle growth and bone growth are numerous as they both share a similar mechanical signaling mechanism(the actin cytoskeleton).  Zinc has also been implicated as an aromatase inhibitor.  Now to optimize growth estrogen should be around a certain level.  Now we're not sure what that level is but estrogen is probably too low pre-puberty when growth is slow, optimal when growth is at it's maximum rate, and too high when growth slows down.  So, if you measure growth rate and growth starts to slow down that's when estrogen inhibition by mechanisms like Zinc should be induced.  What other effects does Zinc have on height?

Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes.

"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. 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."

Zinc fingers are coordinators of Zinc ions.  Zinc is clearly key for chondrocyte proliferation.

" Zfp521 expression around mesenchymal condensations [occurs] as early as E12.5, in the perichondrium and in early chondrocytes, and in the developing growth plate"

"PTHrP (1-34) increased Zfp521 expression dose-dependently and time-dependently".  Forskolin increased Zfp521 expression as well.

" Gαs/cAMP/PKA signaling pathway couples PTHrP to Zfp521 expression."

"Zfp521 down-regulates PTHR1 expression in pre-hypertrophic chondrocytes"

"Deletion of Zfp521 decreased the expression of cyclin D1 and increased the expression of Runx2 and several Runx2 target genes. Bcl-2 expression decreased and caspase-3 activation increased when Zfp521 was absent."

"The decreased cell proliferation[due to inhibition of Zfp521] is chondrocyte-specific as it was not seen in fibroblastic- or osteoblastic cells"

"mice with Col II promoter-driven Runx2 overexpression exhibit accelerated hypertrophic differentiation and premature cartilage mineralization, and overexpression of Runx2 in primary chondrocytes increased matrix calcification"

" deleting cyclin D1 and overexpressing Runx2 both cause a postnatal thinning of the growth plate similar to that in the Zfp521 cKO mice, consistent with functional interaction of the molecules. "

Zinc finger protein 521, a new player in bone formation

"Zfp521, a 30-zinc finger protein, is highly expressed at the periphery of mesenchymal condensations and in developing bones. In these structures it is expressed in chondroblasts, prehypertrophic chondrocytes, the periosteum, osteoblasts, osteoblast precursors, and osteocytes. Forced expression of Zfp521 in osteoblasts in vivo increases bone formation and bone mass, whereas preliminary data suggest that germline deletion leads to osteopenia. In contrast, overexpressing Zfp521 in vitro antagonizes, and knockdown favors, osteoblast differentiation and nodule formation. Zfp521 expression is inhibited by bone morphogenetic protein-2 and stimulated by parathyroid hormone-related protein. Mechanistically, Zfp521 binds to Runx2, repressing its transcriptional activity. Zfp521 both opposes the progression of precursors and promotes the maturation and function of mature osteoblasts. The balance between Zfp521 and Runx2 may therefore contribute to the regulation of osteoblast differentiation and bone formation."

Zfp521 inhibits Runx2 which helps induce chondrocytes to ossify(chondrocytes to differentiate into bone cells).  The fact that BMP-2 inhibits Zfp521 could be why too much BMP-2 inhibits height growth.  Parathyroid Hormone stimulating Zfp521 could be a mechanism as to how teriparatide can increase height.

Zinc-deficient diet decreases fetal long bone growth through decreased bone matrix formation in mice

"This study evaluated the effects of zinc on skeletal development during fetal development in pregnant ICR mice fed a zinc-deficient (3 mg/kg) or zinc-adequate (30 mg/kg) diet. We also included a group pair-fed with the zinc-deficient group to control for decreased appetite due to zinc deficiency. Developing fetuses at embryonic day 18.5 were removed by cesarean section, and the skeletal development was evaluated by histological analysis as well as by body weight and longitudinal growth measurement. Reduced maternal food intake in the zinc-deficient and pair-fed groups resulted in a marked and significant (P < .05) decrease in fetal weight compared to that of the zinc-adequate group. However, fetal length retardation in the pair-fed group was less marked than in the zinc-deficient group, suggesting that reduced supply of zinc from maternal circulation may play a role in longitudinal growth through skeletal development. The fetal developing tibia of the zinc-deficient group showed marked shortening of diaphysis and a mild narrowing of the hypertrophic chondrocyte zone width with increased osteoclast number, but there was no influence on the mineralization of bone matrix. This may be the result of reduced activation of osteoblasts and maturation of chondrocytes with increased osteoclastic activity, suggesting that zinc deficiency during the fetal development has a greater impact on the matrix formation of bone than the mineralization of bone matrix."

Optimal Zinc levels are critical for height growth and stimulating Zfp521 may increase height growth(through a mechanism like Teriparatide).

"The number of osteoclasts was significantly higher in the tibia of fetuses from dams fed the zinc-deficient diet, as compared to the zinc-adequate group."

Interaction of dietary zinc and intracellular binding protein metallothionein in postnatal bone growth.

"Zinc and its binding protein, metallothionein (MT), are important in regulating growth and development, and yet it is unclear how dietary Zn and MT interact in regulating bone growth. Here, 3.5-week female MT-I&II knockout (MT(-/-)) and wild type (MT(+/+)) mice were fed diets containing 2.5 (limiting, Zn-L), 15 or 50 mg Zn/kg (Zn adequate) for 5 or 9 weeks, and effects were analysed on structure and function of growth plate and metaphysis, two structures important for bone growth. Zn limitation did not affect bone growth in MT(+/+) mice. However, MT(-/-) mice, having lower Zn concentrations in plasma and long bone, showed growth retardation as demonstrated by lower body length gain, shorter and smaller tibia/femur, lower chondrocyte proliferation, reduced metaphysis heights, but increased osteoclast densities on trabecular bone, particularly in mice fed Zn-L diet. Interestingly, mRNA expression of MT-I&II was induced in the growth plate of MT(+/+) mice fed the Zn-L diet possibly compensating for Zn limitation. Growth plate MT-III expression increased in MT(-/-) mice fed the adequate Zn diet, whereas metaphyseal MT-III was significantly upregulated in MT(-/-) mice fed Zn-L diet, possibly as a compensatory mechanism or exacerbating effects of Zn limitation. Consistent with the increased osteoclast numbers, a higher ratio of RANKL/OPG gene expression was found in bone of mutant mice fed lower Zn diets. These results indicate that interaction between dietary Zn and endogenous MT is important for maximal bone growth, and MT is particularly important in the regulation of Zn pool for bone growth during moderate Zn limitation."

You can compensate by lower Zinc levels with increased levels of metallothionein, a zinc binding protein.

The resting zone height was maximized at 15 mg Zn/kg versus 2 and 50 mg.  Hypertrophic zone height was reduced at 50mg.  The authors did not find this significant but this indicates the possibility of an equilibrium dose of zinc for height.  Cell proliferation was maximized at 2.5mg.

"Zn limitation in the present study (2.5 mg Zn/kg diet) did not appear to cause bone growth retardation and alter the growth plate structures and heights of primary bone by the ends of 5 and 9 weeks"

Zfp521 antagonizes Runx2, delays osteoblast differentiation in vitro, and promotes bone formation in vivo.

"Zfp521, a 30 C2H2 Kruppel-like zinc finger protein, is expressed at high levels at the periphery of early mesenchymal condensations prefiguring skeletal elements and in all developing bones in the perichondrium and periosteum, in osteoblast precursors and osteocytes, and in chondroblast precursors and growth plate prehypertrophic chondrocytes. Zfp521 expression in cultured mesenchymal cells is decreased by BMP-2 and increased by PTHrP, which promote and antagonize osteoblast differentiation, respectively. In vitro, Zfp521 overexpression reduces the expression of several downstream osteoblast marker genes and antagonizes osteoblast differentiation. Zfp521 binds Runx2 and represses its transcriptional activity, and Runx2 dose-dependently rescues Zfp521's inhibition of osteoblast differentiation. In contrast, osteocalcin promoter-targeted overexpression of Zfp521 in osteoblasts in vivo results in increased bone formation and bone mass. We propose that Zfp521 regulates the rate of osteoblast differentiation and bone formation during development and in the mature skeleton, in part by antagonizing Runx2."

Here's a picture of the bone of Zfp521 overexpression mice:

You can see an increase in bone volume(which includes height).  Overexpressing Zfp521 inhibits osteoblastic differentiation so it likely inhibits hypertrophic chondrocytes from differentiating into bone cells giving them more time to grow.  It's not clear what effect overexpressing Zfp521 would have in stem cells.

So you can likely grow taller by stimulating Zfp521 by a means such as Teriparatide.

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia.

"Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) and is characterized by widening of the metaphyses, reduction of long bone length, and short stature. A transgenic mouse expressing this mutation under the collagen α1(II) promoter has been generated to investigate the mechanisms responsible for this chondrodysplasia. We recently identified zinc finger protein 521 (Zfp521) as a downstream target gene of PTHrP signaling. Interestingly, loss of Zfp521 from chondrocytes leads to reduced cell proliferation and increased differentiation in the growth plate. Specifically ablating Zfp521 from Jansen chondrocytes could sufficiently rescue the chondrodysplasia phenotype. Zfp521 expression is up-regulated in Jansen mouse growth plate chondrocytes and PTHR1 is required for Zfp521 expression. Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length. Zfp521 is required downstream of PTHR1 signaling to act on chondrocyte proliferation, differentiation, and cell death."

Evidence that equilibrium levels of Zfp521 and other Parathyroid Horomones are needed to maximize height growth.

"Loss of Zfp521, specifically in chondrocytes, leads to a reduction in proliferation and an increase in differentiation in growth plate development"<-In turn proliferation rate and differentiation rate have to be optimal for optimal height growth.

"Zfp521 expression is up-regulated in the growth plate of Jansen mice"<-Indicating that too much Zfp5261 causes dwarfism.

Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature.

"Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc-deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age-matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level; Zip8 mRNA expression negatively correlated with growth hormone level during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min."

Clonodine triggers the release of GH.

" As a bivalent cationic ion, zinc cannot permeate through the biological membrane freely."

"Zinc transporters are largely assigned to two metal-transporter families in mammalian: Zip and ZnT. Zip members facilitate zinc influx into cytosol from the outside of cells or from the lumen of intracellular compartments. The ZnT family is also known as cation diffusion facilitator; its members facilitate zinc efflux from cytosol to the outside of cells or transport the cytosolic zinc into intracellular organelles"

"Zip13 knockout mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblast. Mice lacking Zip14 exhibit growth retardation and impaired gluconeogenesis. Mice deficient for ZnT5 showed poor growth and a decrease in bone density due to impairment of osteoblast maturation to osteocyte."

Zip1 and Zip2 positively correlated with Growth Hormone Level whereas Zip8 and Znt1 were negatively correlated.

Zip2 expression was higher in children with short stature than healthy controls.  Zip6 levels were lower than that of healthy controls(Zip6 had a minor positive correlation with GH levels).  Zip8 levels were lower in short stature than healthy controls.  That was all during the growth Hormone provocation tests where Growth Hormone release was stimulated.

"High expression of Zip2 mRNA may import more zinc into cytosol and cause extracellular zinc level decreased. Further, decrease of extracellular zinc arouses the physiological growth hormone secretion. Our inference is consistent with previous report that exposure to micromolar concentrations of zinc caused significant decrease in GH expression in rainbow trout"

1 comment:

  1. The problem with zinc is that it is toxic already at low doses. Teripatide, apart from being hard to get hold of without a prescription, gives an increased risk of osteosarcoma.