C-type natriuretic peptide restores impaired skeletal growth in a murine model of glucocorticoid-induced growth retardation.
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 4weeks 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.
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: yohueda@kuhp.kyoto-u.ac.jp.
Yohei
Y
Ueda
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: ayasoda@kuhp.kyoto-u.ac.jp.
Akihiro
A
Yasoda
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: yui_y@kuhp.kyoto-u.ac.jp.
Yui
Y
Yamashita
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: kani.kani.yugo@kbd.biglobe.ne.jp.
Yugo
Y
Kanai
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: kehirota@kuhp.kyoto-u.ac.jp.
Keisho
K
Hirota
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: ichiroy@kuhp.kyoto-u.ac.jp.
Ichiro
I
Yamauchi
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: kndcocoa@kuhp.kyoto-u.ac.jp.
Eri
E
Kondo
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: uyoriko@kuhp.kyoto-u.ac.jp.
Yoriko
Y
Sakane
Department of Maxillofacial Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: yama0821@kuhp.kyoto-u.ac.jp.
Shigeki
S
Yamanaka
Department of Maxillofacial Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: knakao@kuhp.kyoto-u.ac.jp.
Kazumasa
K
Nakao
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: tfujii@kuhp.kyoto-u.ac.jp.
Toshihito
T
Fujii
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Electronic address: inagaki@kuhp.kyoto-u.ac.jp.
Nobuya
N
Inagaki
D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000633:toxicity*; D006130:Growth Disorders / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D055114:X-Ray Microtomography / Q000379:methods
D005938:Glucocorticoids; D020098:Natriuretic Peptide, C-Type
C-type natriuretic peptide (CNP); Glucocorticoid; Growth retardation; Skeletal growth