Abstract
C-type natriuretic peptide (CNP) and its high affinity receptor-B are expressed in fetal bones. Here we show that CNP accelerates longitudinal growth of fetal rat metatarsal bones in organ culture by several mechanisms. First, CNP stimulates chondrocyte proliferation in the proliferative zone as assessed by [3H]thymidine incorporation. Second, CNP stimulates cell hypertrophy as assessed by quantitative histology. Third, CNP stimulates cartilage matrix production as assessed by incorporation of 35S04 into glycosaminoglycans. Natriuretic peptide receptor-B contains an intracellular guanylyl cyclase catalytic domain. We therefore hypothesized that cyclic GMP (cGMP) would reproduce the effects of CNP on fetal bones. Consistent with this hypothesis, we found that 8-Br-cGMP, like CNP, stimulates longitudinal growth and glycosaminoglycan synthesis. However, unlike CNP, cGMP inhibits proliferation of growth plate chondrocytes and has no effect on hypertrophy. We conclude that CNP stimulates longitudinal bone growth by increasing chondrocyte proliferation, chondrocyte hypertrophy, and cartilage matrix production. cGMP, a second messenger for CNP, reproduces some but not all of the effects of CNP, suggesting that other signal transduction mechanisms may also be involved.
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Abbreviations
- CNP:
-
C-type natriuretic peptide
- cGMP:
-
cyclic GMP
- NPR-B:
-
natriuretic peptide receptor-B
- BNP:
-
brain natriuretic peptide
- E20:
-
embryonic day 20
References
Iannotti JP 1990 Growth plate physiology and pathology. Orthop Clin North Am 21: 1–17
Suda M, Ogawa Y, Tanaka K, Tamura N, Yasoda A, Takigawa T, Uehira M, Nishimoto H, Itoh H, Saito Y, Shiota K, Nakao K 1998 Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide. Proc Natl Acad Sci USA 95: 2337–2342
Suda M, Tanaka K, Fukushima M, Natsui K, Yashoda A, Komatsu Y, Ogawa Y, Itoh H, Nakao K 1996 C-type natriuretic peptide as an autocrine/paracrine regulator of osteoblast. Biochem Biophys Res Commun 223: 1–6
Yasoda A, Ogawa Y, Suda M, Tamura N, Mori K, Sakuma Y, Chusho H, Shiota K, Tanaka K, Nakao K 1998 Natriuretic peptide regulation of endochondral ossification: evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. J Biol Chem 273: 11695–11700
Koller KJ, Goeddel DV 1992 Molecular biology of the natriuretic peptides and their receptors. Circulation 86: 1081–1088
Minamino N, Aburaya M, Kojima M, Miyamoto K, Kangawa K, Matsuo H 1993 Distribution of C-type natriuretic peptide and its messenger RNA in rat central nervous system and peripheral tissue. Biochem Biophys Res Commun 197: 326–335
Sudoh T, Minamino N, Kangawa K, Matsuo H 1990 C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 168: 863–870
Drewett JG, Garbers DL 1994 The family of guanylyl cyclase receptors and their ligands. Endocr Rev 15: 135–162
Lincoln TM, Komalavilas P, Boerth NJ, Mac-Millan-Crow LA, Cornwell TL 1995 cGMP signaling through cAMP and cGMP dependent protein kinases. Adv Pharmacol 34: 305–322
Mancilla E, De Luca F, Uyeda J, Czerwiec F, Baron J 1998 Effects of fibroblast growth factor-2 on longitudinal bone growth. Endocrinology 139: 2900–2904
Bagi CM, Miller SC 1992 Dose-related effects of 1,25-dihydroxyvitamin D3 on growth, modeling, and morphology of fetal rat metatarsals cultured in serum free medium. J Bone Miner Res 7: 29–40
Bagi CM, Burger EH 1989 Mechanical stimulation by intermittent compression stimulates sulfate incorporation and matrix mineralization in fetal mouse long-bone rudiments under serum-free conditions. Calcif Tissue Int 45: 342–347
Espiner EA, Richards AM, Yandle TG, Nicholls MG 1995 Natriuretic hormones. Endocrinol Metab Clin North Am 24: 481–509
Hagiwara H, Sakaguchi H, Itakura M, Yoshimoto T, Furuya M, Tanaka S, Hirose S 1994 Autocrine regulation of rat chondrocyte proliferation by natriuretic peptide C and its receptor, natriuretic peptide receptor-B. J Biol Chem 269: 10729–10733
Levin ER 1993 Natriuretic peptide C-receptor: more than a clearance receptor. Am J Physiol 264: E483–E489
Jikko A, Murakami H, Yan W, Nakashima K, Ohya Y, Satakeda H, Noshiro M, Kawamoto T, Nakamura S, Okada Y, Suzuki F, Kato Y 1996 Effects of cyclic adenosine 3′,5′-monophosphate on chondrocyte terminal differentiation and cartilage-matrix calcification. Endocrinology 137: 122–128
Pfeiffer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fasler R 1996 Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science 274: 2082–2086
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Mericq, V., Uyeda, J., Barnes, K. et al. Regulation of Fetal Rat Bone Growth by C-Type Natriuretic Peptide and cGMP. Pediatr Res 47, 189 (2000). https://doi.org/10.1203/00006450-200002000-00007
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DOI: https://doi.org/10.1203/00006450-200002000-00007
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