Response of plasma CNP forms to acute anabolic and catabolic interventions in growing lambs

Abstract

, we have recently shown that plasma NT-proCNP is strongly correlated with skeletal growth and markers of bone formation and is reversibly reduced by glucocorticoids. The effects on CNP of other catabolic or anabolic factors, known to affect skeletal growth, are unknown. Accordingly, we have studied the response of plasma CNP forms to acute catabolic (caloric restriction) and anabolic [growth hormone (GH) stimulation] interventions in lambs and related the findings to circulating IGF-I levels, growth velocity, and markers of bone formation. Lambs fed a reduced caloric intake (25% of normal) for 6 days exhibited reduced live weight, plasma urea, and IGF-I (P Ͻ 0.001 for all) compared with control lambs. Basal levels of NT-proCNP (40.1 Ϯ 0.9 pmol/l) fell promptly to a nadir (28.1 Ϯ 0.8 pmol/l, P Ͻ 0.001) on day 6, returning rapidly to basal levels upon refeeding. Although plasma alkaline phosphatase (ALP) fell (P Ͻ 0.001), reductions in metacarpal growth velocity were not significant within the 12-day period of study. In contrast to caloric restriction, long-acting bovine recombinant GH (2.5 mg/kg on days 0 and 6), as expected, increased plasma IGF-I more than twofold above control for 12 days (P Ͻ 0.001). Growth velocity did not differ during the 30 days of observation, and, consistent with unchanged growth velocity, plasma NT-proCNP and ALP were also unaffected. In conclusion, CNP synthesis and markers of bone formation are acutely sensitive to catabolism but unaffected by doses of GH that fail to stimulate skeletal growth. skeleton; bone growth; malnutrition; growth hormone; insulin-like growth factor I; amino-terminal pro-C-type natriuretic peptide IN CONTRAST TO THE CIRCULATING CARDIAC HORMONES atrial natriuretic peptide and B-type natriuretic peptide, C-type natriuretic peptide (CNP) acts locally in a variety of tissues, and its sites of synthesis are more diverse (10). Among others, CNP is synthesized in vascular endothelial, brain, and reproductive tissues and in skeletal tissue. In bone, the CNP signaling pathway is essential to endochondral bone growth as shown in both rodents (9) and humans (1). In keeping with its mainly paracrine action, transorgan CNP gradients are low (8) and plasma concentrations are barely detectable in normal health (7,15,17,34). Together these facts greatly limit study of the hormone's regulation and role in vivo. With the use of a novel marker of CNP synthesis [amino-terminal pro-CNP (NTproCNP); see Ref. 29], readily measurable in human and ovine plasma, we have shown recently that this stable product of the CNP gene is strongly correlated with skeletal growth and markers of bone formation (30). Furthermore, plasma NTproCNP levels, along with linear growth and markers of bone formation, are rapidly and reversibly reduced by short-term glucocorticoid administration (30). As well as indicating that CNP synthesis is subject to day-to-day regulation, these findings serve to validate the use of NT-proCNP in studies of the growing skeleton.The potential of other catabolic (11, 16) or...

Plasma Amino-Terminal Pro C-Type Natriuretic Peptide in the Neonate: Relation to Gestational Age and Postnatal Linear Growth

“…We have recently identified a novel marker of CNP synthesis [aminoterminal pro C-type natriuretic peptide (NTproCNP)], which is readily measurable in normal plasma (3). Using this stable product of the CNP gene as a marker of CNP synthesis in tissues, we have shown in both children and lambs (4) that the plasma concentration of NTproCNP is strongly correlated with skeletal growth and markers of bone formation, and is reversibly inhibited by glucocorticoids and caloric restriction (5). Noting the greatly elevated concentrations of NTproCNP in human umbilical plasma at parturition (6), we hypothesized that plasma concentrations of NTproCNP, a putative marker of cartilage growth, is inversely related to gestational age (GA) and positively correlated with postnatal linear growth velocity in neonates.…”

Effect of Cortisol on C-Type Natriuretic Peptide in Ovine Pregnancy: Differential Responses in Fetal and Placental Tissues

“…In postnatal life, there is increasing evidence that CNP synthesis within the growth plate or closely related tissue is strongly correlated with linear growth velocity (7). CNP is inhibited by catabolic interventions such as glucocorticoid administration (7) and caloric restriction (9), which also reduces circulating CNP forms in the fetal lamb (10). In this study, the increase in fetal plasma cortisol concentrations was much smaller than that normally associated with slowed fetal growth before birth (19) or demonstrated slow fetal growth earlier in gestation (20).…”

“…Although shown to be essential to postnatal linear growth in both rodents (4) and humans (5), CNP production has also been found to correlate strongly with linear growth velocity in lambs and throughout all phases of linear growth in humans (6 -8). In rapidly growing lambs, catabolic interventions such as caloric restriction (9) and high doses of glucocorticoids (7), well-recognized inhibitors of linear growth, rapidly and reversibly reduce circulating forms of CNP and markers of bone formation. Similar reductions in CNP forms occur in the fetus during maternal caloric restriction (10) or glucocorticoid administration (6).…”

“…Peptide standards were made from synthetic human proCNP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), taking into account the purity data supplied (Chiron Technologies, Victoria, Australia).Within-and between-assay coefficients of variation were 4.9 and 6.4%, respectively, at 22 pmol/L.…”

Acute inflammation in young children inhibits C-type natriuretic peptide

“…Second, and perhaps more important, circulating concentrations of CNP peptides in healthy growing children are largely sourced from growth plate-related tissues (4,9), which are absent in adults. Both CNP production and linear growth can be rapidly reduced in lambs or children by factors known to impair growth, such as nutrient deficiency (21) or high doses of glucocorticoids (3). Because small (contrived) increases in plasma cortisol for a period of 10 d in fetal lambs also lower NTproCNP (22), stress associated increases in cortisol could contribute to the suppressed levels of CNP we observed.…”