title: Circulating C-type natriuretic peptide (CNP) rescues chondrodysplastic CNP knockout mice from their impaired skeletal growth and early death.
abstract: C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Fujii
authors.forename: Yasato
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasoda
authors.forename: Eri
authors.initials: E
authors.lastname: Kondo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Takuo
authors.initials: T
authors.lastname: Nambu
authors.forename: Naotestu
authors.initials: N
authors.lastname: Kanamoto
authors.forename: Masako
authors.initials: M
authors.lastname: Miura
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D002806:Chondrodysplasia Punctata / Q000097:blood* / Q000235:genetics / Q000401:mortality; D024043:Collagen Type II / Q000235:genetics; D024121:Collagen Type X / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020098:Natriuretic Peptide, C-Type / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D009924:Organ Culture Techniques; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D015996:Survival Rate; D013977:Tibia / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013997:Time Factors
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D024121:Collagen Type X; D018809:Proliferating Cell Nuclear Antigen; D020098:Natriuretic Peptide, C-Type