Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength

Jerid W. Robinson, Nicholas C. Blixt, Andrew Norton, Kim C. Mansky, Zhou Ye, Conrado Aparicio, Brandon M. Wagner, Andrew M. Benton, Gordon L. Warren, Sundeep Khosla, Dana Gaddy, Larry J. Suva, Lincoln R. Potter

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

C-type natriuretic peptide (CNP) activation of guanylyl cyclase (GC)-B, also known as NPR2, stimulates cGMP synthesis and bone elongation. CNP activation requires the phosphorylation of multiple GC-B residues and dephosphorylation inactivates the receptor. GC-B7E/7E knockin mice, expressing a glutamate-substituted, “pseudophosphorylated,” form of GC-B, exhibit increased CNP-dependent GC activity. Since mutations that constitutively activate GC-B in the absence of CNP result in low bone mineral density in humans, we determined the skeletal phenotype of 9-week old male GC-B7E/7E mice. Unexpectedly, GC-B7E/7E mice have significantly greater tibial and L5 vertebral trabecular bone volume fraction, tibial trabecular number, and tibial bone mineral density. Cortical cross-sectional area, cortical thickness, periosteal diameter and cortical cross-sectional moment of inertia were also significantly increased in GC-B7E/7E tibiae. Three-point bending measurements demonstrated that the mutant tibias and femurs had greater ultimate load, stiffness, energy to ultimate load, and energy to failure. No differences in microhardness indicated similar bone quality at the tissue level between the mutant and wildtype bones. Procollagen 1 N-terminal propeptide and osteocalcin were elevated in serum, and osteoblast number per bone perimeter and osteoid width per bone perimeter were elevated in tibias from the mutant mice. In contrast to mutations that constitutively activate GC-B, we report that mutations that enhance GC-B activity only in the presence of its natural ligand, increase bone mass, bone strength, and the number of active osteoblasts at the bone surface.

Original languageEnglish (US)
Article number115320
JournalBone
Volume135
DOIs
StatePublished - Jun 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant R01GM098309 to LRP, a University of Minnesota Foundation Bridge Grant to LRP, a University of Minnesota-Mayo Clinic Partnership grant to LRP and SK, a University of Minnesota Academic Health Center Faculty Research and Development Grant to LRP and CA, NIHT32DK007203 Grant to JWR, NIHT32AR050938 Grant to NCB, and Grants from the Fund for Science and the Hormone Receptor Fund to LRP. National Institutes of Health Grant 5R01CA166060-05 to LJS. We thank Drs. Laurinda Jaffe, Leia Shuhaibar and Siu-Pok Yee for generating the GC-B7E/7E mice and for many helpful discussions. We also thank Dr. Joan E. Bechtold for constructive comments on the manuscript. Finally, we are grateful to Jim Herrick and Donna Jewison in the Tissue Engineering and Biomaterials Laboratory at the Mayo Clinic for performing histomorphometric analysis. The authors have declared that no conflict of interest exists.

Funding Information:
This work was supported by National Institutes of Health Grant R01GM098309 to LRP, a University of Minnesota Foundation Bridge Grant to LRP, a University of Minnesota -Mayo Clinic Partnership grant to LRP and SK, a University of Minnesota Academic Health Center Faculty Research and Development Grant to LRP and CA, NIHT32DK007203 Grant to JWR, NIHT32AR050938 Grant to NCB, and Grants from the Fund for Science and the Hormone Receptor Fund to LRP. National Institutes of Health Grant 5R01CA166060-05 to LJS. We thank Drs. Laurinda Jaffe, Leia Shuhaibar and Siu-Pok Yee for generating the GC-B 7E/7E mice and for many helpful discussions. We also thank Dr. Joan E. Bechtold for constructive comments on the manuscript. Finally, we are grateful to Jim Herrick and Donna Jewison in the Tissue Engineering and Biomaterials Laboratory at the Mayo Clinic for performing histomorphometric analysis.

Publisher Copyright:
© 2020 Elsevier Inc.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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