title: Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice.
abstract: C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.
authors.affiliation: Pharmaceutical Research Department I, Research Division, Chugai Pharmaceutical Company, Shizuoka, Japan.
authors.forename: Takei
authors.initials: T
authors.lastname: Kake
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kitamura
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Adachi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsushita
authors.forename: Toshihito
authors.initials: T
authors.lastname: Fujii
authors.forename: Eri
authors.initials: E
authors.lastname: Kondo
authors.forename: Takanori
authors.initials: T
authors.lastname: Tachibe
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawase
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasoda
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015519:Bone Density / Q000502:physiology; D001846:Bone Development / Q000502:physiology*; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006614:Hindlimb / Q000033:anatomy & histology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020098:Natriuretic Peptide, C-Type / Q000097:blood* / Q000235:genetics; D009929:Organ Size; D010012:Osteogenesis / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011509:Proteoglycans; D012333:RNA, Messenger; D020098:Natriuretic Peptide, C-Type; D006162:Guanylate Cyclase