Calciumfluor does stimulate p42 MAPK which stimulates chondrogenesis.Differential regulation of chondrogenic differentiation by the serotonin2B receptor and retinoic acid in the embryonic mouse hindlimb.
"Retinoic acid (RA) synthesizing and metabolizing enzymes are coordinately expressed with serotonin 2B (5-HT2B)[we've learned about Serotonin possibly having a height increasing before] receptors at sites of epithelial-mesenchymal (E-M) interaction in the mouse embryo. The promoter of the 5-HT2B receptor contains potential RA response element (RAREs) as well as an AP-2 site. Because both retinoid and serotonergic signaling have been implicated in the regulation of chondrogenic differentiation, the present study investigated whether these signals may work together to regulate this morphogenetic process in hindlimb bud micromass cultures. Results indicate that 5-HT promotes [35S]sulfate incorporation (chondrogenic differentiation) by activation of 5-HT2B receptors, which use the mitogen activated protein kinase (p42 MAPK) signal transduction pathway, whereas RA dose-dependently inhibits sulfate incorporation and promotes expression of RARbeta, which could lead to inhibition of p38 MAPK. No evidence was found to support the possibility that RA negatively regulates expression of 5-HT2B receptors. Taken together, these results suggest that 5-HT and RA may act as opposing signals to regulate chondrogenic differentiation in the developing hindlimb, possibly mediated by different MAPK signal transduction pathways."
"5-HT receptor antagonists have been shown to differentially down-regulate cartilage proteoglycan core protein, a marker of cartilage matrix. 5-HT exerts dose-dependent stimulatory effects on levels of insulin-like growth factor-1 (IGF-1), and inhibitory effects on cell proliferation, mediated by 5-HT receptors that activate the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. Activation of 5-HT receptors that either negatively regulate cAMP or activate the Gq-coupled 5-HT2B receptor, promotes cell proliferation in these cultures."
"Serotonin (5-HT) promotes chondrogenic differentiation in hindlimb micromass cultures." "Epithelial 5-HT uptake sites coincide with areas of chondrogenic differentiation in mesenchyme"
"Serum-free hindlimb MMCs were treated with different doses of 5-HT (10−6 M, 10−8 M), together with nialamide (a monoamine oxidase inhibitor) and L-cysteine (an antioxidant), to prevent degradation of 5-HT. Both doses of 5-HT significantly increased [35S]sulfate incorporation, indicative of maturation of cartilage matrix" "IGF-1 significantly promoted [35S]sulfate incorporation"<-So maybe 5-HT and IGF-1 stimulate chondrogenesis by both stimulating sulfate incorporation.
"various 5-HT receptor agonists, including 8-OH-DPAT (5-HT1A) and SC53116 (5-HT4), increase levels of IGF-1, which itself can promote chondrogenesis"
"Activation of the p42/44 MAPK pathway is involved in the positive regulation of chondrogenic differentiation by 5-HT2B receptors in hindlimb cultures."
"RA[Vitamin A] negatively regulates chondrogenic differentiation, without promoting cell death or decreasing
cell proliferation"
"The 5-HT2B receptor activates phospholipase C beta (PLC-β)[LSJL upregulates PLC], causing hydrolysis of phosphatidylinositol bisphosphate (PIP2) to generate diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG then activates protein kinase C (PKC). In tumor cells and cell lines expressing the 5-HT2B receptor, activation of this receptor causes PKC to activate the p42/p44 MAPK pathway by means of p21 ras"
Serotonin increases chondrogenesis via the p42/p44 MAPK pathway so therefore maybe the p42/p44 pathway can increase chondrogenesis.
"The 5-HT2B receptor activates phospholipase C beta (PLC-β)[LSJL upregulates PLC], causing hydrolysis of phosphatidylinositol bisphosphate (PIP2) to generate diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG then activates protein kinase C (PKC). In tumor cells and cell lines expressing the 5-HT2B receptor, activation of this receptor causes PKC to activate the p42/p44 MAPK pathway by means of p21 ras"
Serotonin increases chondrogenesis via the p42/p44 MAPK pathway so therefore maybe the p42/p44 pathway can increase chondrogenesis.
FMS*Calciumfluor specifically increases mRNA levels and induces signaling via MAPK 42,44 and not FAK in differentiating rat osteoblasts.
"The continuous exposure of differentiating rat osteogenic cells (ROB) to FMS*[The homeopathic compound of resonance FMS*Calciumfluor] modulates the level of expression of mRNAs for 7 of the 8 osteogenic markers tested. Alkaline phosphatase (AP), osteocalcin (OC), metalloproteinases (MMP-2 and -14), procollagenase C (BMP-1), biglycan (BG) and integrin 1 are expressed at higher levels in FMS*-treated osteoblasts than in control cultures. MMP-2 and -14 mRNA are not down-modulated at mineralization. Also, the pattern of expression induced by FMS* for some of these genes (BMP-1, BG and integrin 1) is changed, but collagen type I (Coll I) mRNA levels are not affected by treatment with FMS*. This suggests that FMS* modulates mRNA levels and that this is not generalized, but gene(s) specific. We also report that exposure to FMS* rapidly and transiently induces activation of mitogen-activated protein kinases (MAPKs) 42,44 in populations of early osteoblasts[so it may activate it in stem cells as well], but not in pre-osteoblasts, with a cell differentiation stage-dependent and pertussis toxin (PTX)-sensitive response. Subsequent to FMS* MAPK signaling activation, an increase in AP and MMP-14 mRNA is detected, which is also inhibited by PTX, suggesting that FMS* activation of MAPK signaling could be an early event required for the induction of these genes. Exposure to FMS* does not cause changes in the activity of p125 (FAK)-mediated signaling."
Here's an article that links Fluoride to Serotonin:
"The continuous exposure of differentiating rat osteogenic cells (ROB) to FMS*[The homeopathic compound of resonance FMS*Calciumfluor] modulates the level of expression of mRNAs for 7 of the 8 osteogenic markers tested. Alkaline phosphatase (AP), osteocalcin (OC), metalloproteinases (MMP-2 and -14), procollagenase C (BMP-1), biglycan (BG) and integrin 1 are expressed at higher levels in FMS*-treated osteoblasts than in control cultures. MMP-2 and -14 mRNA are not down-modulated at mineralization. Also, the pattern of expression induced by FMS* for some of these genes (BMP-1, BG and integrin 1) is changed, but collagen type I (Coll I) mRNA levels are not affected by treatment with FMS*. This suggests that FMS* modulates mRNA levels and that this is not generalized, but gene(s) specific. We also report that exposure to FMS* rapidly and transiently induces activation of mitogen-activated protein kinases (MAPKs) 42,44 in populations of early osteoblasts[so it may activate it in stem cells as well], but not in pre-osteoblasts, with a cell differentiation stage-dependent and pertussis toxin (PTX)-sensitive response. Subsequent to FMS* MAPK signaling activation, an increase in AP and MMP-14 mRNA is detected, which is also inhibited by PTX, suggesting that FMS* activation of MAPK signaling could be an early event required for the induction of these genes. Exposure to FMS* does not cause changes in the activity of p125 (FAK)-mediated signaling."
Here's an article that links Fluoride to Serotonin:
Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation.
"MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that functions upstream of the MAP kinases and IkappaB kinase. Phosphorylation is believed to be a critical component for MEKK3-dependent signal transduction, but little is known about the phosphorylation sites of this MAP3K. To address this question, point mutations were introduced in the activation loop (T-loop), substituting alanine for serine or threonine, and the mutants were transfected into HEK293 Epstein-Barr virus nuclear antigen cells. MEKK3-dependent activation of an NF-kappaB reporter gene as well as ERK, JNK, and p38 MAP kinases correlated with a requirement for serine at position 526. Constitutively active mutants of MEKK3, consisting of S526D and S526E, were capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK, suggesting that a negative charge at Ser526 was necessary for MEKK3 activity[phosphorylation adds a negative charge] and implicating Ser526 as a phosphorylation site[Ser526 activates MAP3K pathway]. An antibody was developed that specifically recognized phospho-Ser526 of MEKK3 but did not recognize the S526A point mutant. The catalytically inactive (K391M) mutant of MEKK3 was not phosphorylated at Ser526, indicating that phosphorylation of Ser526 occurs via autophosphorylation. Endogenous MEKK3 was phosphorylated on Ser526 in response to osmotic stress[LSJL induces osmotic stress]. In addition, phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro, whereas dephosphorylation of Ser526 was mediated by protein phosphatase 2A and sensitive to okadaic acid and sodium fluoride. Finally, the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526. In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins."
"the presence of PP2A inhibitors such as okadaic acid or sodium fluoride in cell extracts containing transfected MEKK3 prevented dephosphorylation of Ser526"<-Fluoride prevents dephosphorylation of Ser526 and do keeps the MAPK pathway running.
Here's a study that shows Fluoride can alter chondrogenesis:
Here's a study that shows Fluoride can alter chondrogenesis:
[Evaluation of the repair process in mechanically injured rat bone stimulated by sodium fluoride with non-toxic doses].
"The influence of sodium fluoride on the course of repair process in the mechanically injured rat bone was studied. Thirty six male Wistar rats aged 5 months, weighing 460-540 g were investigated. The animals lived under standard conditions and were fed ad libidum with the standard LSM food including 0.7 mg/kg of fluorine on the average. The animals randomly divided into 3 groups that comprised study and control groups, 6 rats each. The rats in the first group were given water with 20 mg (1.05 mmol) of sodium fluoride per kg of body weight for 24 h over a period of 2 weeks--group Ia. In the second group--IIa--animals were given water with sodium fluoride at a dose of 1.5 mmol/kg b.w./24 h for a period of 4 weeks. In the third group--IIIa--the animals were given sodium fluoride in a dose of 1.5 mmol/kg b.w./24 h for a period of 6 weeks. The rats from the control groups I, II and III were given water without sodium fluoride for the period of 2, 4 and 6 weeks, respectively. At the beginning of the experiment a hole was drilled in both femoral bones in rat under barbiturate anaesthesia. According to the protocol the rats underwent ether euthanasia after 2, 4 and 6 weeks after surgery and the following samples were collected: blood from the heart for biochemical studies and both femoral bones for biochemical and histological studies. The following parameters were evaluated in blood serum: fluorine, calcium, magnesium contents, serum concentrations of urea, creatinine, bilirubin and activity levels of enzymes: aspartate aminotransferase, alanine aminotransferase, cholinesterase, base phosphatase. Fluorine, calcium magnesium and zinc contents were estimated in bone samples. The concentration of fluorine ions in animal serum after 2, 4 and 6 weeks of experiment increased significantly as compared with the corresponding controls. The highest fluorine concentrations were observed in serum of rats supplemented with NaF for 6 weeks. The fluorine concentrations in the bone tissue and fresh and dried granulation tissues in all studied groups also revealed statistically significant increase as compared to the controls. The rats fed with sodium fluoride for the period of 6 weeks revealed statistically significant increase of serum magnesium concentration as compared to the remaining study groups. Bone magnesium concentrations in animals fed with NaF for the period of 2 and 6 weeks were higher as compared to the corresponding control groups, with the highest differences observed after 6 weeks of experiment. Animals fed with sodium fluoride for the period of 6 weeks revealed increased serum calcium concentrations as compared to the study groups after 2 and 4 weeks of experiment. Similar results were achieved in bone tissue samples. The use of sodium fluoride led to accelerated chondrogenesis process in the area of insufficiently perfused bone."
So Calcium Fluoride may increase height by increasing chondrogenesis by stimulating the p42/p44 MAPK pathway. However, most of the studies on fluoride have used sodium fluoride and not calcium fluoride. Most of the studies have also tested for osteogenesis and not chondrogenesis.
"The influence of sodium fluoride on the course of repair process in the mechanically injured rat bone was studied. Thirty six male Wistar rats aged 5 months, weighing 460-540 g were investigated. The animals lived under standard conditions and were fed ad libidum with the standard LSM food including 0.7 mg/kg of fluorine on the average. The animals randomly divided into 3 groups that comprised study and control groups, 6 rats each. The rats in the first group were given water with 20 mg (1.05 mmol) of sodium fluoride per kg of body weight for 24 h over a period of 2 weeks--group Ia. In the second group--IIa--animals were given water with sodium fluoride at a dose of 1.5 mmol/kg b.w./24 h for a period of 4 weeks. In the third group--IIIa--the animals were given sodium fluoride in a dose of 1.5 mmol/kg b.w./24 h for a period of 6 weeks. The rats from the control groups I, II and III were given water without sodium fluoride for the period of 2, 4 and 6 weeks, respectively. At the beginning of the experiment a hole was drilled in both femoral bones in rat under barbiturate anaesthesia. According to the protocol the rats underwent ether euthanasia after 2, 4 and 6 weeks after surgery and the following samples were collected: blood from the heart for biochemical studies and both femoral bones for biochemical and histological studies. The following parameters were evaluated in blood serum: fluorine, calcium, magnesium contents, serum concentrations of urea, creatinine, bilirubin and activity levels of enzymes: aspartate aminotransferase, alanine aminotransferase, cholinesterase, base phosphatase. Fluorine, calcium magnesium and zinc contents were estimated in bone samples. The concentration of fluorine ions in animal serum after 2, 4 and 6 weeks of experiment increased significantly as compared with the corresponding controls. The highest fluorine concentrations were observed in serum of rats supplemented with NaF for 6 weeks. The fluorine concentrations in the bone tissue and fresh and dried granulation tissues in all studied groups also revealed statistically significant increase as compared to the controls. The rats fed with sodium fluoride for the period of 6 weeks revealed statistically significant increase of serum magnesium concentration as compared to the remaining study groups. Bone magnesium concentrations in animals fed with NaF for the period of 2 and 6 weeks were higher as compared to the corresponding control groups, with the highest differences observed after 6 weeks of experiment. Animals fed with sodium fluoride for the period of 6 weeks revealed increased serum calcium concentrations as compared to the study groups after 2 and 4 weeks of experiment. Similar results were achieved in bone tissue samples. The use of sodium fluoride led to accelerated chondrogenesis process in the area of insufficiently perfused bone."
So Calcium Fluoride may increase height by increasing chondrogenesis by stimulating the p42/p44 MAPK pathway. However, most of the studies on fluoride have used sodium fluoride and not calcium fluoride. Most of the studies have also tested for osteogenesis and not chondrogenesis.
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