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

TitleMale mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength
Authors
Issue Date2020
Citation
Bone, 2020, v. 135, article no. 115320 How to Cite?
AbstractC-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.
Persistent Identifierhttp://hdl.handle.net/10722/319051
ISSN
2023 Impact Factor: 3.5
2023 SCImago Journal Rankings: 1.179
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRobinson, Jerid W.-
dc.contributor.authorBlixt, Nicholas C.-
dc.contributor.authorNorton, Andrew-
dc.contributor.authorMansky, Kim C.-
dc.contributor.authorYe, Zhou-
dc.contributor.authorAparicio, Conrado-
dc.contributor.authorWagner, Brandon M.-
dc.contributor.authorBenton, Andrew M.-
dc.contributor.authorWarren, Gordon L.-
dc.contributor.authorKhosla, Sundeep-
dc.contributor.authorGaddy, Dana-
dc.contributor.authorSuva, Larry J.-
dc.contributor.authorPotter, Lincoln R.-
dc.date.accessioned2022-10-11T12:25:09Z-
dc.date.available2022-10-11T12:25:09Z-
dc.date.issued2020-
dc.identifier.citationBone, 2020, v. 135, article no. 115320-
dc.identifier.issn8756-3282-
dc.identifier.urihttp://hdl.handle.net/10722/319051-
dc.description.abstractC-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.-
dc.languageeng-
dc.relation.ispartofBone-
dc.titleMale mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bone.2020.115320-
dc.identifier.pmid32179168-
dc.identifier.scopuseid_2-s2.0-85081730238-
dc.identifier.volume135-
dc.identifier.spagearticle no. 115320-
dc.identifier.epagearticle no. 115320-
dc.identifier.isiWOS:000530069000013-

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