Biology 466    Unsolved Problems Fall 2010

How to Cure and/or to Avoid Osteoporosis:

A list of every possibility I could invent (& some overlaps)



1) Kill osteoclasts, or weaken them. (specific methods for doing this will be discussed below)

2) Inhibit the specific proteolytic enzymes that osteoclasts secrete.

3) Inhibit the process of secretion of these enzymes by osteoclasts.

4) Inhibit the secretion of acid by osteoclasts. Or inhibit all secretion of hydrochloric acid everywhere in the body. You can get along without stomach acid. Treatments may already have been developed to inhibit stomach acid secretion, as part of efforts to treat ulcers and acid reflux.

5) Neutralize the acid that osteoclasts secrete (so that bone mineral isn't dissolved).

6) Develop a drug or treatment that causes osteoclasts to be killed by the acid that they secrete (or killed by their own enzymes). Or cause the process of acid secretion to damage osteoclasts.

7) Weaken whatever protective mechanisms osteoclasts use to avoid being damaged by acid.

8) Invent a drug that is converted into a poison where acidity is high (lower than some threshold pH).

9) Attract osteoclasts to move away from bone. Or cause them to be repelled by bone. ("chemotaxis")

10) Inhibit adhesion proteins by which osteoclasts attach to bone along their edges, so that the acid and the proteolytic enzymes will leak out of the space between the bone surface and the osteoclasts.

11) Inhibit the directionality of secretion (of either acid or enzymes) so that much or most of it is pumped out of the osteoclasts on the side away from their attachment to bone.

12) Incorporate into bone some selectively poisonous drug (analogous to the antibiotic aureomycin) that, instead of killing bacteria, will damage or kill any osteoclasts that try to digest areas of bone that contain this drug. There should be more research into what it is about aureomycin that causes it to get incorporated into bone, so that this property may be deliberately designed into other drugs, like bisphosphamides.

13) Electric voltages could attract osteoclasts away from bone, especially in vulnerable locations.
(Only macrophages and osteocytes are attracted toward the positive electrode.)

14) Make monoclonal antibodies specific for some (any!) protein that only osteoclasts have. Find one of the long list of "Cluster of Differentiation" antibodies that has some specificity for osteoclasts, fuse B-lymphocytes that make this antibody with myeloma cells, thereby creating a source.

15) Stimulate more ossification, any way you can, to compensate for destructive effects of osteoclasts.

16) Maybe bone that includes substantial amounts of strontium, yttrium, or zirconium, in place of part of the calcium, would be more resistant to osteoclasts.

17) If the hydrophobic adhesion specificity peculiar to macrophages is also true of osteoclasts, then there must be some way to take advantage of this special property to inhibit the adhesion of osteoclasts to bone.

18) Osteoclasts are multinucleate cells, believed to form by fusion of mononuclear leucocytes (=macrophages), then either inhibit cell-cell fusion, or...

19) Cause cell-cell fusion to kill fusing cells, or...

20) Cause osteoclasts to fuse with other differentiated cell types (other than macrophages and other osteoclasts), because when any differentiated cell fuses with a cell of a different cell type, then the product of the cell-cell fusion loses both sets of differentiated properties (i.e. turns off transcription of both sets of luxury genes).

21) Incorporate some sort of buffer of acidity into bone, so that pH is kept high.

22) Find a reliable, consistent way to isolate osteoclasts into tissue culture from bones of embryonic chickens, and use this as a way of directly testing effectiveness of bisphosphonate chemicals, instead of starting with tests on hundreds of hospitalized patients, as is now done.

23) Synthesize bisphosphonates with every possible side chain. Find out what properties the side chains need to have in order to stimulate programmed cell death, using the bioassay you developed in # 22.

24) Inject short-lived osteoclast-killing drugs along the sides of major bones, so that effects are concentrated there, with less damage to the esophagus & mouth.










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