Defects in a protein called alphaV beta3 integrin appear to contribute to the development of osteoporosis, and these effects can be reversed by enhancing a protein called macrophage-colony-stimulating factor(M-CSF), according to Schoolof Medicine researchers.
The study appeared in the first March issue of the Journal of Clinical Investigation and was published online March 4.
“Because of our previous research with these proteins, new drugs already are in clinical trials,” said lead investigator Steven L. Teitelbaum, M.D., the Wilma and Roswell Messing Professor of Pathology and Immunology.
“But we still do not understand how these proteins interact to affect bone-cell development. This study brings us significantly closer to determining that mechanism.”
Osteoporosis, a condition that results in weakened, brittle bones, afflicts roughly 50 percent of Caucasian and Asian women above age 65. It develops when bone is broken down at a faster rate than it is synthesized.
Therefore, curing the disease and others like it depends on understanding osteoclasts — cells responsible for eroding bone — and determining why they sometimes become overly active.
Teitelbaum’s team previously determined that M-CSF helps unspecialized bone cells develop into mature osteoclasts. Without enough M-CSF to encourage osteoclast growth, animals develop abnormally dense bone.
Similarly, it is known that blocking alphaV beta3 integrin in animal models causes failure of osteoclast function. However, it is unclear precisely how M-CSF or alphaV beta3 integrin influence osteoclast development.
The absence of beta 3 (part of the alphaV beta3 integrin) in precursor cells has a curiously different effect on cells in a petri dish compared with cells in livinganimals.
When grown in a dish, abnormally few osteoclasts develop, and those that do develop are dysfunctional. In animals, however, precursor cells lacking beta3 produce abnormally high numbers of osteoclasts.
“This paradox suggests that something in the living animal interacts with beta3 during the process of osteoclast differentiation,” Teitelbaum said.
His team discovered the interaction may involve M-CSF. When the researchers took precursor cells from mice lacking beta3 and put them in a petri dish, very few became osteoclasts.
But when levels of M-CSF were increased, the stunted growth effect was reversed. Furthermore, they determined that a particular structure on the surface of the cell (c-Fms tyrosine 697, a component of the protein designed to bind to M-CSF) appears to be largely responsible for this interaction.
“The interaction betweenM-CSF and alphaV beta3 integrin is intriguing and may help explain some of the less-understood aspects of animal models of osteoporosis,” Teitelbaum said.
Because of this interaction, Teitelbaum and his colleagues also explored whether alphaV beta3 integrin and M-CSF are involved in the same signaling pathway that causes precursor cells to differentiate into osteoclasts.
They found increased levels of M-CSF also restored activity of externally regulated kinases (ERKs) and a protein calledc-Fos, which are critical for stimulating the cascade of events that lead to bone-cell differentiation.
Because alphaV beta3 integrin also is known to contribute to the activation of ERKs and c-Fos, the team concluded that the alphaV beta3 integrin and M-CSF collaborate in the process of osteoclast differentiation.