RESUMO
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.
Assuntos
Desenvolvimento Ósseo/fisiologia , Condrodisplasia Punctata/sangue , Peptídeo Natriurético Tipo C/sangue , Osteogênese/fisiologia , Animais , Animais Recém-Nascidos , Peso Corporal/genética , Peso Corporal/fisiologia , Desenvolvimento Ósseo/genética , Condrodisplasia Punctata/genética , Condrodisplasia Punctata/mortalidade , Colágeno Tipo II/genética , Colágeno Tipo X/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Peptídeo Natriurético Tipo C/genética , Peptídeo Natriurético Tipo C/farmacologia , Técnicas de Cultura de Órgãos , Osteogênese/genética , Antígeno Nuclear de Célula em Proliferação/análise , Taxa de Sobrevida , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento , Tíbia/metabolismo , Fatores de TempoRESUMO
The rare condition of chondroplasia punctata is illustrated by two patients. The very different manifestation and course of the disease in these two patients confirms Spranger et al's (1971) view that it is an heterogeneous disease which can be divided into two types. The rhizomelic type is characterised by well marked punctate cartilage calcification, shortening of the extremities, deformities of the metaphyses and epiphyses, frequent cataracts and a fatal outcome. In the Conradi-Hünermann-type the changes are less marked and the patients may survive. In order to classify the disease correctly, radiological examination in early childhood is desirable.
