46: calcium regulation

Transcribed by Vandeep Bagga May 1st, 2014

Organ Systems Lecture 46 – Physiology of Calcium Regulation by Dr. Schiff

Dr. Schiff – Ok. Now, this hour, or what's left of it, I will be discussing calcium, which is another thing that has to be regulated, blood plasma levels of calcium have to be regulated as part of regulating homeostasis because if you have too much calcium, you will get increased transmitter release at synapses amongst other things. If you have too little calcium, sometimes permeability to excitable membranes break down and you might get spontaneous action potential generation. If it’s really low, I'm not really going into that sort of thing, but basically perhaps the most important part of it is, remember that a significant fraction, perhaps about half of the calcium that's involved in cardiac contraction comes from the extracellular fluid (ECF). Some comes from the sarcoplasmic reticulum (SER) and some comes from the ECF. And so what happens is, if your calcium is too high or too low, it will effect the strength of the heartbeat, of the cardiac contraction. So generally as part of our homeostasis, we want to maintain calcium, calcium is in the plasma as normally about 2.5 mM.

Now most of the calcium in our bodies of course, is in bone. So you have plasma calcium and bone. And there's an equilibrium there. Because once you're fully grown, and if you're not doing anything special to change your skeletal structure, or during pregnancy or breastfeeding you need more calcium in your plasma, this is generally an equilibrium. And this breakdown of bone to dump calcium into the plasma is done by osteoclasts, its called osteoclasis. And the storage of calcium in bone is done by osteoblasts. And what we’re trying to do is regulate the plasma calcium concentration at a certain fixed level of about 2.5 mM.

Now there are 2 other roots by which you can add or subtract calcium, at least potentially. One is, if you eat something with calcium in it, so food, milk, cheese, not spinach! Unlike what Popeye always says, most of the calcium in spinach is in the form of an oxylate salt, which is insoluble, so you don’t resorb it at all. But you can get calcium from dairy products and so on. And the other possibility is losing it into urine. So for the most part, the calcium movements in your body, if you're in a steady state, that is, you are fully grown. This is maintained with an equilibrium here. Just as glucose levels are maintained by an equilibrium between glucagon and insulin. But at some point you may need more calcium to enter this equilibrium, for example if you're pregnant or breast feeding, you’re building a whole new skeleton. Or if you're a kid and you're still growing, you need more calcium to build your own skeleton. Or if you have a fracture that's healing, you might need more calcium for that purpose. Normally, we don’t absorb very much calcium in our diets. And as a result, we lose very little or no calcium in our urine. There are basically no other pathways here. And there are 3 hormones that are involved in calcium regulation, parathyroid hormone (PTH), calcitonin, and vitamin D. And each has its own site of action, or sites of action. And they all effect various aspects of this.

Calcitonin is secreted by cells within the thyroid, these interfollicular cells, and between the follicles of the thyroid gland, its sort of embedded there. But again, they're not under any specific hormonal or nervous control, what they do is respond

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to calcium concentration in the plasma. And if you have low calcium in the plasma, it promotes calcitonin secretion. And what does calcitonin do? Where does it act? What effect does it have? And so on. Well calcitonin acts on osteoblasts, which form bones, and you want to slow that down because if your calcium in your plasma is too low already, you don’t want to take more of it out to make more bone, so its inhibitory of the osteoblasts. Ok? That's the simplest of these 3 hormones in terms of mode of action, it acts apparently on 1 place and it inhibits osteoblasts from making more bone so that at least it keeps your plasma calcium from being depleted further. It stimulated in response to low calcium, but there's something else you have to keep in mind. As I said before, this osteoblast/osteoclast equilibrium is a balanced equilibrium for the most part in a person that's not growing or doing something else complicated. And so, the osteoclasts are breaking down bone, the osteoblasts are building up bone, and what you’ve got is a balance between them under normal conditions, so theirs is equal traffic in both directions. If you inhibit calcitonin, if calcitonin inhibits the osteoblasts, the osteoclasts will continue to run and outrace any osteoblastic activity, which is inhibited, so the major effect here will be to release calcium from bone into the plasma. Now if it doesn’t speed up the osteoclastic…

*student question*

Dr. Schiff – PTH raises, wait a minute, you’re right, I drew the arrow in the wrong direction, to the wrong target. Please erase everything for the last minute and a half, ok? Its too early in the morning for me actually. Osteoblasts. Ok, now. Do I at least have the arrows in the right direction? Ok.

What calcitonin does, that's where I started off in the wrong direction. If you have high calcium in your plasma, then what's going to happen is, you don’t want to dump any more calcium into the plasma. Which means, you don’t want to break down bone and dump. I'm looking at something backwards here. Why is my brain not functioning?! Alright, calcitonin, parafollicular cells in the thyroid, it stimulated by high calcium, and it inhibits the osteoclasts. Ok. So calcitonin, inhibits the osteoclasts so you don’t add more calcium to the blood. In fact, the osteoblasts, since they continue to do what they're doing, will continue to remove calcium from the blood. Ok. My sincere apologies.

PTH has the opposite effect, PTH is secreted when you have low calcium. I should have listed them in the other order. If you have low plasma calcium, you secrete PTH from the parathyroid glands and there are like 6 or 4 or 8 of them embedded in your thyroid. And PTH promotes the osteoclasis, and breakdown of bone so you dump more calcium into the bloodstream. Ok.

Now, parathyroid has 2 other functions and 2 other sites of actions. Oh actually I should mention this, because, after all, so few good news items come out of NYUCD. 1 of them really should be plugged. PTH stimulates osteoclasts but indirectly because if you look for them and isolate the osteoclasts, there are no PTH receptors

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on them. So PTH doesn’t act directly on the osteoclasts, its eventual effect is to stimulate osteoclasis, but what happens is that the PTH actually acts on osteoblasts, there are receptors for PTH on osteoblasts, which are very specific receptors that tell the osteoblasts, they don’t stimulate them at all, they tell the osteoblasts to secrete a peptide called osteoclast stimulating factor, or stimulating hormone, it’s a paracrine type thing, that is it travels only in the local tissue. And the osteoblasts release this osteoclast activating hormone, which then indirectly activates the osteoclasts. In any case. The only reason this is worth mentioning is that this factor was discovered, well not in this building, but the Weismann building. By a fellow on the faculty here named Howard Grobe, who then left NYU. *laughter* He joined the faculty at Adelphi. And has since passed away. Ok.

So that's the 1 effect of PTH. The 2nd effect of PTH is here. If you're secreting PTH, it means your calcium must be low. So the last thing in the world you want to do, is to piss it away. In the distal part of the DCT, PTH acting as a transcription stimulator, stimulates the production of a Ca ATPase, which reabsorbs whatever calcium is in the filtrate so that less calcium is lost in the urine. Interestingly, calcium is 1 of the few solutes that not freely filtered at the glomerulus because calcium, being doubly charged, is hard to get across a lipid membrane, so the calcium that is filtered is a little bit lower than the calcium in the plasma. The calcium in the filtrate is then 90% reabsorbed as you go through the nephron, mostly in the PCT, some in the DCT. So about 90% of the calcium is reabsorbed by the time you reach the distal part of the DCT. PTH induces this calcium ATPase, which causes about the next 5% to be reabsorb, so only 5% is lost in the kidney, in the urine. The other 5% we’ll get to in a minute, because under normal conditions, when you have low plasma calcium, you don’t lose any calcium in the urine, and that's involved in vitamin D, but here you have PTH prevents, I’ll put an X there, loss of, or diminishes loss of calcium in the urine.

There's a 3rd effect of PTH. And that has to do with the development, the maturation, the formation, of the active form of vitamin D. I’ve gone through this already, you have cholesterol, UV light, cholecalciferol, liver, 25-hydroxy-vitamin D, and then in the kidney, there are 2 alternative hydroxylases, one produces 1,25-dihydroxy-vitamin D, and one produces 24,25-dihydroxy-vitamin D. And this 1 is eventually garbage, althought given billions of years of evolution, maybe it does have a function we haven’t figured out yet. And this is the active hormone, the active form of vitamin D. And what does vitamin D do? Well, while we’re talking about the kidney, 1,25-dihydroxy-vitamin D also induces a calcium transporter and you end up effectively all of the calcium that's in the filtrate, so there's no calcium left in the urine.

The 2nd effect of vitamin D is to allow calcium absorption of your small intestine, because there's no point in drinking of all that milk, or eating all that yogurt or cheese or whatever, if you do not have the vitamin D to enable your intestines to absorb it. And remember you only make this, 1,25-dihydroxy-vitamin D in the presence of PTH. So, as an aside, there are 3 places of action for PTH, 1 is in bone, by indirectly acting on osteoblast receptors but stimulating osteoclasts. Second in the

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distal part of the kidney, and 3rd, here, to enable the kidney, these are the peritubular capillary cells apparently, to do the 1 hydroxylation of 25-hydroxy-vitamin D to form the 1,25-dihydroxy form, which is the active vitamin D hormone. There are also 3 other sites of action of vitamin D. One is in the intestines. One is the distal part of the DCT. There's a 3rd effect, but this may sound a little backwards.

What 1,25-dihydroxy-vitamin D does is it inhibits production of PTH. Now wait a minute. You’re only producing this form of vitamin D, this active vitamin D, in the presence of low calcium. In the presence of low calcium, you want to produce PTH, right? In fact, it’s the PTH that allows you to form 1,25-dihydroxy-vitamin D. So what advantage would it be to inhibit production of PTH? Because you don’t want too much bone resorption, because remember what bone is made of. It’s a calcium phosphate salt, and you don’t want too much bone resorption. You are already getting some calcium from food and you're not losing any, you're doing some bone resoprtion, but you don’t want too much bone resoprtion, because that would raise the plasma concentration of phosphates. Which would then precipitate with calcium, and form little crystals in your blood stream, which is not a healthy thing to have.

So, just to bring it all together, calcitonin is the simplest thing because it has 1 site of action and 1 function, which I finally got right. PTH acts in 3 different places to do 3 different things, DCT, the formation of vitamin D, and activating osteclasis indirectly. And vitamin D has 3 different actions, it allows calcium absorption and it prevents loss of calcium in the urine, but it also inhibits the production, or it provides negative feedback regulation of the production of PTH.

Now, as I mentioned somewhere before, in a totally different topic, one of the problems that can occur is inability to form vitamin D, the active form, somewhere along the steps of its synthesis. And for a long time, during the industrial revolution, this was the problem, right here. Because in the industrial cities, there was so little sunshine reaching the ground, and that's your main source of vitamin D. Dicken’s never wrote about tanning salons! People would develop Ricketts. Ricketts come from an inadequate vitamin D formation, and as a result of that, you end up with inadequate calcium absorption from the intestines and especially if you're a growing person, or a pregnant person, or a breastfeeding person, you need additional calcium to add to milk or to add to the baby skeleton that's growing or to grow your own skeleton as you go from being born this big, to growing up to that big. You’re building more skeleton. So children are most effected by lack of sunshine and they would develop a syndrome called Ricketts, which would involve inadequate bone calcification, bowed legs, stuff like that. And 1 of the characteristics symptoms of Ricketts are what are referred to rachitic knobs. And that is as the rib cage is forming, where the ribs insert on the sternum, you have overgrowth, for some reason the lack of vitamin D there's an overgrowth of the cartilage at that joint, so if you look at the bare chest of such a child, you’ll see at each rib where it meets the sternum, a large knob of overgrown cartilage. Possibly because the growing ends of the ribs never fully calcified so they're making more cartilage. I don’t know the exact

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mechanism. I bet Dr. Craig knows. He seems like the type of person who would, I’ll ask him. Ok so there you go!

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46: calcium regulation

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