Our body functions in a wonderful manner. Apparently, it has a natural cycle of building bone in order to maintain skeletal strength. Also, our body breaks down the bones whenever there is requirement for calcium needs. Moreover, this cycle is believed to have been delicately balanced. However, diseases like osteoporosis break down too much bone without sufficient bone replacement which may perhaps result in bone fractures.
Scientists from Duke University have put forward a targeted approach through which drugs may be able to fight osteoporosis and other degenerative bone diseases. Diane Gesty-Palmer along with her team have discovered a novel mechanism of bone formation in mice which seems to work without stimulating the complementary bone breakdown.
The science appears to concentrate on two biochemical pathways arising from a cell surface receptor called G-protein coupled receptor (GPCR). Supposedly, this is the largest family of cell surface receptors. Additionally, GPCR seems to be the target of numerous drugs for the treatment of several medical disorders.
For many years, scientists believed that the cellular actions of these receptors may be exclusively controlled by activation of G-protein pathways. However, GPCR discoverer, Duke’s Robert J. Lefkowitz, MD, has also discovered that another molecule, beta-arrestin appears to function like a brake on G-protein activation.
Evidently, his lab is learning about ways so that beta-arrestin can also signal through diverse pathways. This may in turn directly control certain cellular processes. By combining their understanding in bone metabolism and GPCR signaling, Drs. Gesty-Palmer and Lefkowitz have found that beta-arrestin could possibly cause bone to form, even though it blocks receptor activation of the G proteins. They were believed to have discovered that this occurs in the receptor for parathyroid hormone (PTH). PTH is known to regulate the amount of calcium in the body and is used to treat osteoporosis.
Evidently, the experts separated the bone-forming actions of the PTH receptor from its damaging bone-resorbing actions. This seems to have been possible only by turning off G-protein signaling with a PTH analogue called PTH-βarr (for beta-arrestin). They found much less bone was resorbed and overall the amount of bone grew.
“We didn’t anticipate finding bone growth because we thought that once the G-protein coupled pathway was blocked, that bone formation would also be blocked,†says Diane Gesty-Palmer, MD, a Duke Assistant Professor of Endocrinology and Metabolism
“It is commonly believed that the bone-forming actions of the parathyroid hormone receptor are mediated exclusively through G-protein activation,†continues Palmer.
Lefkowitz, James B. Duke Professor in the Departments of Medicine and Biochemistry and Howard Hughes Medical Institute Investigator further stated that, “I think we will find that the beta-arrestin pathways play very important roles in the body. It is scientific convention that the G-protein dependent signaling pathways are the best pharmaceutical targets, but as we are learning more, we see that beta-arrestin dependent pathways also have an impact on physiological processes. Getting others to accept this, however, has been like turning around a battleship — it happens very slowly.â€
“We keep refining the science. With this in vivo study, we have reached the next level of specificity. With what we have learned, we may begin to create the keys to unlock targeted groups of receptors with this higher level of specificity,†continues Lefkowitz.
Lefkowitz claimed that with this refinement, the experts may perhaps also accomplish the control required in order to avoid certain drug side effects.
“We think the next generation of drugs, in this instance for osteoporosis, will behave more as we would like them to,†adds Lefkowitz.
It was observed that Dr. Lefkowitz calls the GPCRs, which he discovered, the 7-transmembrane receptors. Allegedly, this name reflects the distinctive structure of the receptor proteins which weave across the cell membrane seven times. More so, these proteins seem to accommodate the fact that beta-arrestin pathways may also be activated by these receptors.
The findings of the study have been published in the journal, Science Translational Medicine.