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This Article Full Text (PDF) All Versions of this Article: 297/6/E1339    most recent ajpendo.00272.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kake, T. Articles by Nakao, K. PubMed PubMed Citation Articles by Kake, T. Articles by Nakao, K.

RESEARCH ARTICLE

Chronically elevated plasma C-type natriuretic peptide (CNP) level stimulates skeletal growth in transgenic mice.

¹Chugai Pharmaceutical Co., ltd. ²Chugai Pharmaceutical Co., Ltd. ³Kyoto University Graduate School of Medicine

Submitted 30 April 2009 ; revised 8 September 2009 ; accepted in final form 27 September 2009

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 (CMC) 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.

CNP; transgenic mouse; blood level elevation