Biology 466    Unsolved Problems Fall 2010


Unsolved problems related to bone formation, strengthening of bone in response to forces, degeneration of bones when no forces are imposed, healing of broken bones, osteoporosis, cartilage shape, and bone replacement of cartilage.

During all our lives, bone is constantly being deposited by special mesenchymal cells called osteocytes, and just as constantly being destroyed by a special multinucleate kind of macrophages called osteoclasts. When unusually strong forces are imposed on a particular bone, it will become stronger. A good example is the serving arm of professional-level tennis players. The bones in the serving arm will become twice or more stronger than the same person's other arm. It is not known for sure how the cells of bones detect how much force is imposed on them. Without some detection method, it would not be possible for bone to become stronger in response to increased forces. The thin rods of bone running through the marrow (trabeculae) develop along the axes of strongest load, as if drawing a diagram of forces. Furthermore, when people's bones have been subjected to forces in unusual directions, then these trabeculae orient parallel to the directions of maximum force that the individual person had experienced. So this is not just a matter of evolving genes that cause trabeculae to develop in particular axes. What has evolved is some method by which the bone cells detect forces, and more bone is deposited at the locations, and also in the directions, where the forces are strongest.

In principle, increased bone formation could be caused by reduction in the number or activity of osteoclasts, or by increases in the activity of osteocytes, or by a combination of less bone being removed and more bone being deposited. It Isn't known for sure which of these three possible explanations is the true means by which bones and parts of bones are made stronger.

The class of anti-osteoporosis drugs called bisphosphonates were originally intended to favor bone formation and make bone stronger (although before that they were used in industrial quantities to "soften" water used for irrigation of farms). Unexpectedly, it has turned out that they promote death of osteoclasts. Although this does inhibit osteoporosis, the drugs have side effects, probably caused by promoting death of other cell types, including those of the esophagus and the jaw. If you do internet searches for these drugs, you will find lots of dispute, including details of ongoing lawsuits against drug companies. Bisphosphonate drugs include "Fosamax" and "Boniva" and many others. The chemical structures are correctly shown in the Wikipedia article about bisphosphonates, although I doubt everything they say from "Mechanism of action" to the end. For one thing, they are guessing; and for another thing, the guesses betray serious misunderstandings of biochemistry.

Bone consists of one third type I collagen, by weight, tightly packed with crystals of the salt calcium phosphate, which make up nearly all the other 2/3rds, plus some other ions including fluoride. In sections of bone looked at by transmission electron microscopy, both components are clearly visible - the collagen as evenly-striped fibers, and the calcium phosphate as dense black masses. But when you use the same method (TEM sections) to look at osteocytes in areas where more bone is being made, vesicles inside the osteocytes contain lots of collagen fibers, but no evident calcium phosphate crystals. If they were there, you would definitely be able to see them. This creates a paradox, or at least a puzzle: How do cells make bone? It is correct to use the word "secrete" to describe deposition of the 1/3rd of the bone that is collagen. But it cannot be by secretion that they cause formation of the mineral part of bone (the calcium phosphate crystals). If it were secreted, then one would be able to see vesicles containing this salt, which would be easily visible by electron microscopy.

Other methods of creating calcium phosphate salt, outside the cells, need to be considered. For example, you know that cells use ion pumps to transport calcium ions through plasma membranes, and use ATP hydrolysis to transfer the energy to pump the calcium (and other ions, especially sodium). Therefore, let us hypothesize an ATP-driven trans-membrane calcium pump, that also pumps some of the released phosphate ions to the exterior of the cell, enough to raise the local concentrations of both ions enough to create over-saturation. That is one of the kinds of theories that have been considered over the years to explain how bone is "secreted".

Closed extracellular membrane vesicles have often been found concentrated at locations where bone is being made. A theory has been proposed in which these vesicles might serve to concentrate both the phosphate and the calcium ions, by both of them being pumped into the interior of the vesicles, enough to raise both ion's concentrations above saturation. This might be true. There are also other possibilities. A larger question is: By what sorts of methods or experiments can we distinguish which of these mechanisms is actually operating when osteocytes are making bone.

Another set of important questions, related to how bone growth is controlled, involves the generation of voltages as a result of compression and stretching of bone and also cartilage. It has been a popular theory, regarded by many as a fact, that electric voltages are the signals by which physical loads stimulate increased formation of bone.


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