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New targets identified for drugs that could be as beneficial to the skeleton as exercise
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A discovery by investigators at Stanford University could lead to the development of new drugs that provide the same benefits to the skeleton as exercise and could be used to treat patients with osteoporosis.
“We believe that this study takes the field an important step forward in answering a 200-year-old question, ‘How does bone sense mechanical loads?’” Christopher R. Jacobs, PhD, co-author of the study, stated in a press release from the Federation of American Societies for Experimental Biology (FASEB). “Ultimately, we hope that the mechanisms identified in this study can be exploited to develop novel treatments for bone loss and perhaps a large number of other diseases involving the remarkably versatile primary cilia.”
The research was published online in The FASEB Journal.
Signaling mechanisms
The research provides further insight into the identification of the signaling mechanisms used by primary cilia to regulate the capacity of bone cells to sense fluid flow. The investigators showed that bone cells use cilia to activate bone-forming genes in response to mechanical loads, according to the release.
During physical exercise, bone cells are subjected to fluid flow. Primary cilia within these bone cells detect the flow. The investigators studied an enzyme found in bone cells called adenylyl cyclase 6 (AC6), which is compartmentalized within the primary cilia. AC6 quickly inactivates in response to fluid flow, initiating a signaling cascade that leads to increased expression of bone-forming genes, the release noted.
Cyclooxygenase 2 expression
Jacobs and his colleagues exposed bone cells to fluid flow and measured the intracellular levels of cyclic AMP, a signaling molecule synthesized by AC6. They found that the levels decreased after 2 minutes of fluid flow. When they used RNA interference to inhibit primary cilia formation, as well as AC6 production, the levels did not decrease in response to fluid flow.
According to the release, these results suggest that a short bout of fluid flow sufficiently increases expression of cyclooxygenase 2 – a gene important for bone formation. The study also suggests that primary cilia play an important role in diseases such as osteoporosis.
- Reference:
Kwon RY, Temiyasathit S, Tummala P, et al. Primary cilium-dependent mechanosensing is mediated by adenylyl cyclase 6 and cyclic AMP in bone cells [published online ahead of print April 6, 2010]. FASEB J.
It’s easy for doctors to tell osteoporosis patients that they need to get a good workout a few days each week, but the reality is that many patients are too frail to do so. This groundbreaking study details the exact biochemical signals used by bone cells to turn the daily work-out into new bone. This research pinpoints new targets for drugs that will allow physicians to break this cycle of frailty, bone loss and incapacity, so that patients can live longer, healthier and more active lives.
– Gerald Weissmann, MD
Editor-in-Chief, The FASEB Journal
Comment provided in press release
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