Mineralization of bone - essential for its hardness and strength - involves a well orchestrated process in which crystals of calcium phosphate are produced by bone-forming cells and laid down in precise amounts within the bone’s fibrous matrix or scaffolding. If the process is not properly regulated, the result can be too little of the mineral or too much - either of which can compromise bone health. By studying the molecular players in the process, NIAMS-supported scientists are gaining a better understanding of how bone forms and what happens when the process goes awry. Their findings are helping to identify therapeutic targets for problems ranging from osteomalacia (a potentially fatal softening of the bones) to painful bone spurs and spinal stiffening.
The regulation of this process, the researchers have found, relies largely on a substance called inorganic pyrophosphate, which inhibits abnormal calcification. "It is a very small molecule, but it is an important inhibitor of calcification," says José Luis Millán, Ph.D., professor of oncodevelopmental biology at the Burnham Institute for Medical Research in LaJolla, Calif. "It is involved in controlling the right rate, the right pace of calcification in the normal skeleton." Levels of this important bone regulator are controlled by at least three other molecules: nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which produces pyrophosphate outside the cells; ankylosis protein (ANK), which further contributes to the extracelluar pool of pyrophosphate by transporting it from the cell's interior to the cell surface; and tissue nonspecific alkaline phosphatase (TNAP), which breaks down pyrophosphate in the extracellular environment, keeping its levels in check.
If any of these molecules are deficient, problems can occur. The researcher found that mice lacking TNAP (which causes the calcium-regulating pyrophosphate to rise too high), for example, are born with soft bones that don’t calcify properly. Deficiencies of NPP1 or ANK, on the other hand, lead to problems with excessive calcification, such as bone spurs (as seen in osteoarthritis in people) or bone-like hardening of tendons and ligaments of the spine (which is common in people with a form of arthritis called ankylosing spondylitis). By breeding mice that were deficient in TNAP with those deficient in either NPP1 or ANK, however, the researchers were able to create mice with neither too much nor too little calcification. "We were actually able to correct many of the defects that these individual mouse strains would have by themselves," says Millán. These findings suggest that each of these molecules might be therapeutic targets.
Moreover, Millán and his colleagues identified yet another player in the regulation of bone calcification: a protein called osteopontin. In mouse studies, the researchers have found that osteopontin levels are highly correlated with pyrophosphate levels, yet they don't know yet if the two are acting in concert or if one controls the other. That is an issue they hope to address further in future studies. They also hope to discover whether the findings they have made in mice will apply to people.
Their hope is to find therapies that target the mechanism of pyrophosphate production, transport and breakdown to eliminate the problems that come from abnormal - be it too much or to little - calcification.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov. Information on bone and its disorders can be obtained from the NIH Osteoporosis and Related Bone Diseases~National Resource Center; Phone (toll free) 800-624-BONE (2663), or visit https://bones.nih.gov/.
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