Takei Kake1, Hidetomo Kitamura2,3, Yuichiro Adachi4,2, Tetsuro Yoshioka5, Tomoyuki Watanabe2, Hiroaki Matsushita2, Toshihito Fujii5, Eri Kondo5, Takanori Tachibe6, Yosuke Kawase6, Kou-ichi Jishage6, Akihiro Yasoda5, Masashi Mukoyama5, Kazuwa Nakao5
1Pharmaceutical Research Department I, Research Division, Chugai Pharmaceutical Company, Shizuoka, Japan.
2Pharmaceutical Research Department I, Research Division, Chugai Pharmaceutical Company, Shizuoka;
3Project Management Dept.
4Novartis, USA
5Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto; and
6Pharmacology and Pathology Research Center, Chugai Research Institute for Medical Science, Shizuoka, Japan
Tóm tắt
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.
