Bone Formation and Osteoporosis

Biology 446 Unsolved Problems, August 31, 2016

Bone is constantly being destroyed by osteoclasts and made (& RE-made) by osteocytes. The mechanism of bone destruction is secretion of acid and protein-digesting enzymes.
The mechanism of bone formation is secretion of collagen, plus unknown methods for precipitating Calcium phosphate (a very important subject of debate).

Bone (and also the dentine part of teeth) is made of 1/3 type I collagen and 2/3 calcium phosphate (in a crystal form called "calcium apatite", that includes hydroxy and sometimes fluoride ions). The enamel layer of teeth is 98% calcium apatite, and proteins different than collagen (The Wikipedia article on "Tooth enamel" is excellent, accurate, up-to-date and well-illustrated.)

By some unknown method, bones detect strengths and locations of physical forces imposed on them. (For example, the arm bones of a right-handed tennis player become much more dense & stronger.) Bones become weaker when the forces imposed on them are weaker: a big problem for Astronauts.

Note that muscles also enlarge & degenerate in response to local amounts of stress (also heart muscle).

#1) Unsolved problem is what chemical process causes deposition of calcium apatite. (It is never seen inside cytoplasmic vesicles, which means it can't be secreted.) (Maybe crystals are nucleated on "osteoid" proteins that act as if reducing solubility of apatite?).

#2) Unsolved problem is whether force-induced strengthening results from less weakening by osteoclasts, or from increased bone deposition? Try to invent experiments able to distinguish between possibilities.

#3) Unsolved problem is how forces are detected by bone cells? (Which includes detecting locations and directions of forces on the interior bone trabeculae).

A very popular theory is that osteocytes respond to electrical voltages produced by stress. Supposedly, the voltages are produced by piezoelectricity, which is a property of many crystals, (unfortunately not including calcium apatite!).

Voltages can also be generated by "electroosmosis", & my guess is this has been misinterpreted.

Electric stimulation is used clinically to stimulate bone formation {But is still doubtful if it really works}.

If you "Google" "voltage treatment for broken bones" You will find lists of such treatments..


Incidental facts:

Mollusk and Echinoderm skeletons are made of calcium carbonate, not phosphate.

"Bone-Seeking Elements" are those that get incorporated into bone along with calcium. Strontium, samarium, lead, technetium, radium and plutonium. & aureomycin? These are used medically, especially technetium.

Endochondral Ossification: Replacement of embryonic cartilage by bone: Please look at the second illustration in the Wikipedia article about ossification, titled "Primary Center of Ossification, or Growth Plate" and try to figure out what force has flattened the chondrocytes and arranged them into long horizontal rows?

Dermal Bones (such as the roof of the skull) are formed by conversion of dense collagen layers into bone.

Dystrophic Calcification. For example: Tendons often become calcified (notice in Thanksgiving turkeys!)

Atherosclerotic arteries especially in the head, sometimes develop into bone (& even form bone marrow!)

Bone is highly visible by transmission electron microscopy: but is never seen inside osteocytes. Therefore, bone is not secreted, unlike collagen, cartilage and many other materials.

Extracellular membrane vesicles are consistently (always?) found next to places where bone is forming.

Possible methods by which osteocytes cause calcium phosphate precipitation:
* Secreting high concentrations of calcium ions.
* & Catalysis of release of extracellular ATP or other phosphate containing organic compounds.
* Secretion of "osteoid" proteins &/or polysaccharides which somehow decrease solubility of apatite.
* Please invent other possibilities.

You could make a medical discovery of tremendous importance, if you invented a method by which bone formation could be stimulated to occur at chosen locations, and without harmful side effects. A method for decreasing destruction of bone by osteoclasts would also be an enormous breakthrough.

Bisphosphonates were thought to accomplish one or both of these goals. Unfortunately, it turns out that their real effect is to stimulate apoptosis, not only of osteoclasts but also other cell types (with bad side effects). Google "bisphosphonates" Google "Boniva side effects" (evidently censored by drug companies)

Maybe you should invent a way to inhibit fusion of macrophages to form osteoclasts, or to let acid leak through osteoclasts, or leak out under their edges.


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