Dietary Ca or Ca/P during inflammation will increase calcification and microcalcification?

[UG Krishnamurti]

When I am in inflamed state I always felt extremely worse if I drink milk for example. The symptoms I experience were intestinal bleeding (I have Crohn's), extreme scalp hardness, psoriasis getting worse, fatigue, cramping etc. Even just drinking plain mineral water higher in calcium created intestinal bleeding [I've experimented with it just a month ago]. Now, looking back I probably assume this type (or similar kind) of mechanism made me bleed after using D3 supplement [Bleeding again, now after D3 supplement - SUPER CONFUSED]

This is the study which would maybe explain some mechanisms behind it. Apparently, higher dietary Ca & Ca/P would be a bad thing to consume when you are in an inflamed state when/if macrophages are activated.

Ray have also said that when you are in an energy deprived state, calcium will end up going inside the cell.
But I've never heard him saying to be careful with it. In some of my email exchange between us he never considered calcium could be a problem, or recommend caution.

Macrophage-Derived Matrix Vesicles
We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification.
Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.

Proinflammatory Macrophages Release Microcalcification-Generating MVs​

Time-lapse imaging of macrophages loaded with Fluo-3, a calcium indicator, showed vesicle release from membranous protrusions (Figure 2A; provided in Online Movies) and calcium influx after Ca/P stimulation (Figure 2B and 2C). Ca/P-stimulated macrophages released MVs (Mac-MVs) capable of mineralization, with increased calcium content (Figure 2D and 2E), alkaline phosphatase activity (Online Figure VI), and suggested aggregation potential (Figure 2F and 2G).

Mouse macrophages stimulated with Ca/P possessed higher levels of mRNA encoding inducible nitric oxide synthase and interleukin-6 (Figure 2J), markers in mice of a proinflammatory M1 macrophage polarization, whereas M2 markers tended to decrease.

Figure 2. Macrophages release microcalcification-generating matrix vesicles (MVs).
A, Time-lapse imaging of mouse MV release from RAW264.7 (t=0–20 seconds; Online Movie). B and C, The intensity of Fluo-3, a calcium indicator, within human macrophages (hMac) increased with Ca/P stimulation, demonstrating calcium influx on Ca/P stimulation. The arrow represents the x axis on the graph. D and E, Various stimuli induce the release of MVs with increased calcium content from mouse and human macrophages (n=3–7, *P<0.05, **P<0.001, ***P<0.0001; mean±SD). F and G, Macrophage-derived MVs (Mac-MVs) from Ca/P-stimulated mouse macrophages were larger in size and potentially aggregated over time (n=3). H, Ultrastructure of mouse Mac-MVs released in vitro, showing membrane-bound MVs from control cells (top) and calcifying MVs (bottom). I, MVs expressed exosomal markers (TSG101 and CD9). J, Ca/P-stimulated mouse macrophages expressed proinflammatory markers (M1 phenotype; n=3, *P<0.01 vs control). Ca/P=3 mmol/L calcium/2 mmol/L phosphate. ARG1 indicates arginase 1; IL, interleukin; iNOS, inducible nitric oxide synthase; MRC1, mannose receptor, C type 1; and TNF, tumor necrosis factor.

Discussion​

We report a novel pathway of microcalcification that involves macrophage-derived MVs. Concentrations of extracellular Ca and P, similar to those found in serum of CRD patients on dialysis, induced the release of Mac-MVs with higher calcification potential. These findings support the operation of a new additional mechanism of arterial calcification that likely accelerates the excessive intimal and medial calcification associated with CRD. Because of the relative abundance of macrophages over SMCs [Smooth Muscle Cells] in rupture-prone plaques,1 we hypothesize that macrophage-derived MVs participate in the initiation of microcalcification.

The use of compound mutant mice, in addition to gain-of-function and loss-of-function in vitro experiments, permitted dissection of the role of S100A9 in the calcification of macrophage-derived MVs in vivo. Previous studies identified S100A9-positive macrophages in early atherosclerotic lesions and suggested the role of this calcium-binding protein in vascular inflammation.16 The present evidence implicates S100A9 in the mineralization of macrophage-derived MVs.

This study provides new insight into the pathogenesis of vascular calcification, particularly microcalcification, a contributor to the acute thrombotic complications of atherosclerosis.

 

[Giraffe]

If your diet is low in calcium your body will take the calcium from your bones.

 

[UG Krishnamurti]

If your diet is low in calcium your body will take the calcium from your bones.

I don't argue for low dietary calcium but mechanisms through which dietary calcium becomes potentially toxic.
I believe there are certain states, like for example VIT D and VDR issues and imbalances, or inflammatory states where dietary calcium could pose a problem.

 

[SamYo123]

If your diet is low in calcium your body will take the calcium from your bones.

How can that be true for vegans that have no sign of bone issues later in life?

 

[Kvothe]

I don't argue for low dietary calcium but mechanisms through which dietary calcium becomes potentially toxic.
I believe there are certain states, like for example VIT D and VDR issues and imbalances, or inflammatory states where dietary calcium could pose a problem.

These processes are unlikely to be amplified by dietary calcium or high Ca/P ratio. A low calcium intake is usually responsible for abnormal calcium stimulation via parathyroid action. The study doesn't say in any way that this would be stimulated by dietary calcium.

 

[Kvothe]

How can that be true for vegans that have no sign of bone issues later in life?

They usually do, but a good vegan diet can potentially bone protective I guess, with calcium and vitamin K from leafy greens and good mineral waters or shells.

 

[UG Krishnamurti]

How can that be true for vegans that have no sign of bone issues later in life?

I think vegans still get some calcium from fruits and green leafy vegetables. Maybe we don't need it in higher amounts.
Acid-base balance seems to be crucial in osteoblastic and osteoclastic activity.

These processes are unlikely to be amplified by dietary calcium or high Ca/P ratio. A low calcium intake is usually responsible for abnormal calcium stimulation via parathyroid action. The study doesn't say in any way that this would be stimulated by dietary calcium.

Thanks, but what do you think are:
"Ca/P-stimulated macrophages"
"The intensity of Fluo-3, a calcium indicator, within human macrophages (hMac) increased with Ca/P stimulation, demonstrating calcium influx on Ca/P stimulation."
"Various stimuli induce the release of MVs with increased calcium content from mouse and human macrophages"

It clearly states that macrophages have greater calcifying potential in the presence of high extracellular Ca & Ca/P:
"Concentrations of extracellular Ca and P, similar to those found in serum of CRD patients on dialysis, induced the release of Mac-MVs with higher calcification potential."

 

[Beastmode]

How can that be true for vegans that have no sign of bone issues later in life?

For example?

I imagine there isn't enough data to prove this right or wrong, but most older vegans look like ***t and depleted. Maybe the saggy skin that I've seen in them gives me the impression that their bones are probably deteriorating as well.'

I would add, aren't vegans typically high in phosphate, which can make matters worse over time?

 

[SamYo123]

For example?

I imagine there isn't enough data to prove this right or wrong, but most older vegans look like ***t and depleted. Maybe the saggy skin that I've seen in them gives me the impression that their bones are probably deteriorating as well.'

I would add, aren't vegans typically high in phosphate, which can make matters worse over time?

View: https://www.youtube.com/watch?v=8lHU2jZsbv8&feature=emb_title


read the description

 

[Giraffe]

I think vegans still get some calcium from fruits and green leafy vegetables. Maybe we don't need it in higher amounts.
Acid-base balance seems to be crucial in osteoblastic and osteoclastic activity.


Thanks, but what do you think are:
"Ca/P-stimulated macrophages"
"The intensity of Fluo-3, a calcium indicator, within human macrophages (hMac) increased with Ca/P stimulation, demonstrating calcium influx on Ca/P stimulation."
"Various stimuli induce the release of MVs with increased calcium content from mouse and human macrophages"

It clearly states that macrophages have greater calcifying potential in the presence of high extracellular Ca & Ca/P:
"Concentrations of extracellular Ca and P, similar to those found in serum of CRD patients on dialysis, induced the release of Mac-MVs with higher calcification potential."

High extracellular calcium is a symptom. It shows that something is out of whack. Inflammation for example causes high extracellular calcium.

I think that "Ca/P stimulation" means that some cells sense that the concentration is high and react to it.


Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors

Activation of the NLRP3 inflammasome enables monocytes and macrophages to release high levels of interleukin-1β during inflammatory responses. Concentrations of extracellular calcium can increase at sites of infection, inflammation or cell activation. Here we show that increased extracellular calcium activates the NLRP3 inflammasome via stimulation of G protein-coupled calcium sensing receptors. Activation is mediated by signalling through the calcium-sensing receptor and GPRC6A via the phosphatidyl inositol/Ca2+ pathway.

 

[Jessie]

I think as long as you're getting plenty of magnesium the high-calcium intake won't cause much of an issue. If I understand the issue correctly, I believe it's the over accumulation of intracellular calcium that causes the most harm, because the cells can't generate sufficient ATP from it. This happens when our magnesium is low (which could be low due to thyroid).

When magnesium is normal, it keeps extra calcium outside of the cell, and the cells use the magnesium to generate ATP. Magnesium is the body's primary calcium antagonist. There's also other anti-calcium agents, like progesterone, taurine, cyproheptadine, lidocaine, CO2, bicarbonate. Vitamin K2 is needed to transport calcium.