Ossification, calcification and other biological examples of calcium salt formation inside the body

Although I find it hard to believe that "They" still haven't solved such medically-important questions as are outlined below, there was very little net progress for a long time, and may still not be.

Bone and tooth dentin are two-thirds calcium apatite (calcium phosphate, plus some other ions, including fluoride), and one third type I collagen, "woven" tightly together. Tooth enamel is 95% calcium apatite and 5% of proteins very different from collagen. If the element strontium is present, it gets incorporated into bone as if it were calcium. Plutonium is another element that gets specifically incorporated into bone, apparently by the same mechanisms whose normal function is to concentrate calcium ions and precipitate them as calcium phosphate. Scientists who have been spared learning about this strange field often say or write the verb "secrete" as what osteocytes supposedly do to create bone. Collagen fibers really are synthesized by these cells, put into vacuoles and secreted. The calcium salts seem to precipitate among the already secreted collagen fibers of bone, by a still-unknown mechanism that has long been debated.

Other tissues, including tendons and artery walls, somehow get calcium salts precipitated out among their collagen fibers. If you eat a turkey this Thanksgiving, you may have an opportunity to examine and chew on some calcified tendons. The degree of ossification in older people's arteries (especially near the brain, unfortunately) sometimes even become ossified to the extreme degree of developing a bone marrow!

The dentin of teeth is considered to be a special case of bone. One difference is that it gets deposited in thousands of straight parallel lines, with strands of odontoblast cell cytoplasm. Odontoblasts are the tooth version of osteoblasts, but this isn't just a name difference, because the embryological origin is different. Teeth also lack osteoclasts, and do not have the constant dynamic balance of digestion and re-deposition. A major dental problem, seldom if ever discussed in public, is that sometimes osteoblasts invade one or more teeth, and quickly destroy the dentine. This can be induced by bad mechanical damage to teeth, for example in automobile and skate-board accidents, and by excessively intense orthodontia. This was a major subject of research papers presented at that international dental meeting I told you about.

Sea shells are calcium carbonate, rather than phosphate. There are supposed to be some small marine creatures that make skeletons from strontium salts, rather than calcium salts. Nothing would surprise me!

We will now consider some possible (plausible, hypothetical) methods by which living cells could cause calcium phosphate to precipitate out of solution. If you multiply the concentration of calcium times the concentration of phosphate, then this product (in the sense the word product is used in algebra) has to exceed a threshold amount called "the solubility product" in order for precipitation to occur. For any combination of an anion and a cation, there is some particular solubility product. If this number is something like 10 to the minus 14, then that salt is rather insoluble. If it's 10 to the minus 20, then it's a very insoluble salt; and for a rather soluble salt, the solubility product might be 10 to the minus five.

Apart from specific numbers, a key concept is that the relation is multiplicative, in the sense that doubling or tripling the concentration of one ion will reduce by a half or a third the maximum concentration of the other ion that can be in equilibrium with the salt formed when these two ions precipitate out to form their "salt". In the chemist's way of speaking "salt" doesn't just mean sodium chloride, but also any precipitated combination of anions and cations, including calcium phosphate. We will ignore for the moment the phenomenon that in a salt like calcium chloride (CaCl2) and aluminum chloride (AlCl3), you square or cube the chloride concentration in calculating solubility products. In other words, because of the two chlorides in CaCl2 , doubling the chloride solution has the same effect as quadrupling the calcium concentration.

The principles of solubility are important for understanding ossification because hypothetical mechanisms divide into at lease three and a half categories:

a) Methods for locally increasing the calcium concentration so high that it will combine with the ordinary low concentrations of phosphate, and exceed the solubility product;

b) Methods for locally increasing the concentration of phosphate very high, enough for this same solubility product to be exceeded, even with the ordinarily low concentrations of chloride in body fluids.

+) Combinations of both a and b occurring simultaneously at the same locations.

c) Methods for decreasing the (effective?) solubility product (making calcium phosphate less soluble), assuming that this is a logical possibility! The versions of this that I have heard suggested depend on collagen and/or polysaccharides binding to and stabilizing calcium phosphate crystals. I can think of unusually simple experimental tests whether this effect can be produced under a microscope; can you?

a) Some specific theories of type (a)

1) Trans-membrane ion pumps could pump calcium out of cells (using ATP energy) at localized places, maybe invagination, along their outer surface.

2) Trans-membrane ion pumps could pump calcium into vacuoles inside of cells, and maybe pump phosphates into the same vacuoles.

3) Membrane sacs (vesicles) have been reported to be released from osteocytes, with calcium then being actively pumped into these vesicles, producing a high concentration.

b) Some specific theories of type (b)

1) ATP could be hydrolyzed at particular locations, inside or on cells, for the purpose of producing lots of phosphate ions concentrated locally (instead of for transferring energy).

1.5 ) Some other organic phosphate chemicals could be hydrolyzed, instead, releasing phosphate.

2) Phosphate ions could be pumped across plasma membrane, or into vacuoles.

Please invent experiments that could be able to disprove or prove some of these theories.

Please suggest other theories.

Please suggest medical uses, or other implications, of these different theories.

Please consider and discuss whether it's possible to invent or interpret experiments, except in terms of reasonably specific theories about how a biological mechanism works.

Does it change your theories that plutonium and strontium get incorporated into bone?

In designing experiments, how might you take advantage of incorporation of other ions into bone?