دانلود رایگان مقاله بازیابی اختلال رشد اسکلتی پپتید ناتریورتیک نوع C

ABSTRACT

Glucocorticoids are widely used for treating autoimmune conditions or inflammatory disorders. Long-term use of glucocorticoids causes impaired skeletal growth, a serious side effect when they are used in children. We have previously demonstrated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. In this study, we investigated the effect of CNP on impaired bone growth caused by glucocorticoids by using a transgenic mouse model with an increased circulating CNP level. Daily administration of a high dose of dexamethasone (DEX) to 4-week-old male wild-type mice for 4 weeks significantly shortened their naso-anal length, which was restored completely in DEX-treated CNP transgenic mice. Impaired growth of the long bones and vertebrae by DEX was restored to a large extent in the CNP transgenic background, with recovery in the narrowed growth plate by increased cell volume, whereas the decreased proliferation and increased apoptosis of the growth plate chondrocytes were unaffected. Trabecular bone volume was not changed by DEX treatment, but decreased significantly in a CNP transgenic background. In young male rats, the administration of high doses of DEX greatly decreased N-terminal proCNP concentrations, a marker of CNP production. In organ culture experiments using fetal wild-type murine tibias, longitudinal growth of tibial explants was inhibited by DEX but reversed by CNP. These findings now warrant further study of the therapeutic potency of CNP in glucocorticoid-induced bone growth impairment.

4. Discussion

In the present study, we examined the effect of CNP on the impaired skeletal growth in a mouse model for GC-induced growth retardation. We used SAP-Nppc-Tg mice, which have increased circulating CNP levels [19]. We could successfully restore the impaired skeletal growth of a mouse model of GC-treatment with a higher level of circulating CNP. DEX impaired the growth of cranial and appendicular bones but CNP overexpression reversed the impairment of appendicular bone growth. Skull length tended to be lengthened by CNP but skull width was not rescued. Whereas appendicular bones are formed through endochondral ossification, skeletogenesis of cranial bone consists of both endochondral and intramembranous ossifications and cranial bone is widened mainly by intramembranous ossification. CNP is a stimulator of bone growth based on endochondral ossification, and we have previously reported that CNP did not affect skull width using transgenic and knockout mice [29]. We therefore concluded that although DEX impairs both endochondral and intramembranous bone growth, CNP could restore only the endochondral bone growth impaired by DEX. As for the growth of bones formed through endochondral ossification, recovery from DEX-induced growth impairment induced by CNP was stronger in appendicular bones than in vertebrae. The reason for this is not known at present, but the shortness of the longitudinal length and the thinness of the growth plate in each vertebral body may affect the rescue effect of CNP on impaired endochondral bone growth by DEX