US researchers have discovered a new way of growing bone that could open the door to developing new drugs to fight osteoporosis and other degenerative bone diseases by directly intercepting cellular processes that control the formation and breakdown of bone in the body.
The study was led by Dr Diane Gesty-Palmer, Assistant Professor of Endocrinology and Metabolism at Duke University Medical Center in Durham, North Carolina, and is published in the first issue of the new journal Science Translational Medicine, dated 7 October.
Bone is not a “dead” material but a living and dynamic system based on a delicate balance between forming bone and then breaking it down again (resorption). The process maintains skeletal strength and supplies the body’s demand for calcium.
When the delicate balance is disturbed, for instance when the system resorbs bone faster than it can make it, it leads to bone degenerative diseases like osteoporosis, resulting in bone fractures.
In this new study, the researchers have found a new way of generating bone in mice that is not accompanied by bone breakdown.
About 40 per cent of drugs work through what are now called the seven-transmembrane receptors (7TMRs, so named because their receptor structure weaves across the cell membranes seven times). These receptors sense special molecules called ligands (the “keys” that open the “locks” of the receptors) on the outside of cells, and if they are the right ones, activate a signalling pathway inside the cell.
For many years scientists thought that these receptors all worked via a pathway that used so-called heterotrimeric GTP-binding proteins (G proteins). But since then, Duke’s Dr Robert J Lefkowitz, a co-author of the study, discovered another pathway that uses another group of molecules called beta-arrestins that work like a brake on the G proteins.
Bringing together their respective knowledge of these signalling pathways and bone metabolism and working with laboratory mice, Lefkowitz and Gesty-Palmer found that beta-arrestin can stimulate bone formation even though it also blocks receptor activation of the G protein pathways. This happens via the receptor for parathyroid hormone (PTH), which controls the amount of calcium in the body, and is used to treat osteoporosis.
They were then able to selctively stimulate the bone-forming mechanism of the PTH receptor from the bone-resorbing mechanism by turning off the G-protein signals using an analogue of PTH called PTH-Beta-arr (for beta-arrestin).
The result was significantly less bone resorption and a net overall growth of bone.
The researchers concluded that:
“These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists.”
“Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity,” they added.
Gesty-Palmer told the media that:
“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.”
“It is commonly believed that the bone-forming actions of the parathyroid hormone receptor are mediated exclusively through G-protein activation,” she added.
Lefkowitz said he thinks that “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,” he explained, adding that:
“Getting others to accept this, however, has been like turning around a battleship — it happens very slowly.”
Lefkowitz said they keep refining the science, and with this study they reached the next level of refinement.
“With what we have learned, we may begin to create the keys to unlock targeted groups of receptors with this higher level of specificity,” he added.
They may also have reached the stage where it is possible to see how to make drugs that don’t have certain side effects.
“We think the next generation of drugs, in this instance for osteoporosis, will behave more as we would like them to,” said Lefkowitz.
The study was funded by the Arthritis Foundation, the National Institutes of Health (NIH), and Veterans Affairs Medical Administration and supported by the Howard Hughes Medical Institute.
“A beta-Arrestin-Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation.”
Diane Gesty-Palmer, Pat Flannery, Ling Yuan, Leonor Corsino, Robert Spurney, Robert J. Lefkowitz, Louis M. Luttrell.
DOI: 10.1126/scitranslmed.3000071
Sources: Duke University Medical Center, NIH.
Written by: Catharine Paddock, PhD