Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor
- University of Connecticut Health Center, United States
- University of Minnesota, United States
- University of Tübingen, Germany
Abstract
Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.
Article and author information
Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD014939)
- Laurinda A Jaffe
National Institute of General Medical Sciences (R01GM098309)
- Lincoln R Potter
National Institute of Diabetes and Digestive and Kidney Diseases (Postdoctoral training grant:T32DK007203)
- Jerid W Robinson
National Institute of Dental and Craniofacial Research (Postdoctoral training grant:R90DE022526)
- Ninna P Shuhaibar
Fund for Science (Postdoctoral scholarship (mentor)))
- Laurinda A Jaffe
Fund for Science (Postdoctoral scholarship (postdoc)))
- Leia C Shuhaibar
Fund for Science (Research grant)
- Caroline N Dealy
Fund for Science (Research grant)
- Lincoln R Potter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted as approved by the animal care committees of the University of Connecticut Health Center (101395-0519) and the University of Minnesota (1507-32769A).
Reviewing Editor
- Gail Mandel, Oregon Health & Science University, United States
Publication history
- Received: September 22, 2017
- Accepted: December 2, 2017
- Accepted Manuscript published: December 4, 2017 (version 1)
- Version of Record published: December 27, 2017 (version 2)
Copyright
© 2017, Shuhaibar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor
eLife 6:e31343.
https://doi.org/10.7554/eLife.31343
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