Catch-up growth after glucocorticoid excess: a mechanism intrinsic to the growth plate.

Baron, Jeffrey; Klein, Karen Oerter; Colli, M J; Yanovski, Jack A.; Novosad, J A; Bacher, John; Cutler, Gordon B.

doi:10.1210/endo.135.4.7925098

Cited by 106 publications

(28 citation statements)

References 12 publications

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“…Nonetheless, we did not observe any systemic effects of rapamycin. The tibial growth rate was most rapid in the first 4 weeks of the experiment, consistent with prior observations 26. The inhibitory effect of rapamycin on linear bone growth was most pronounced at the peak growth rate during the fourth week of infusion.…”

Section: Discussionsupporting

confidence: 89%

The effect of rapamycin on bone growth in rabbits

Phornphutkul

Lee

Voigt

et al. 2009

Journal Orthopaedic Research

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mTOR is a nutrient-sensing protein kinase that regulates numerous cellular processes. Our prior studies using the mTOR inhibitor, rapamycin, indicate an important role for mTOR in chondrogenesis. We extended our observations to a physiological, in vivo model of bone growth, direct infusion of rapamycin into the proximal tibial growth plates of rabbits. Rapamycin or DMSO vehicle was infused directly into growth plates by an osmotic minipump for 8 weeks. Tibial growth was followed radiographically. At the end of the experiment, growth plates were recovered for histological analysis. Six animals were studied. No untoward effects of rapamycin infusion were found. Bone growth of limbs exposed to rapamycin was slower than control limbs, particularly during the period of most rapid growth. Histological analysis revealed that growth plate height in the rapamycin-infused limbs was reduced. Both the hypertrophic and proliferative zones were significantly smaller in the rapamycin-infused limbs. Direct infusion of rapamycin into proximal tibial growth plates decreased the size of the growth plate and inhibited overall long bone growth. Rapamycin appears to affect both the proliferative and hypertrophic zones of the tibial growth plate. Our results indicate that nutrients may exert a direct effect on long bone growth via mTOR-mediated modulation of chondrogenesis at the growth plate. and suggest that the possible inhibitory effects of rapamycin on skeletal growth warrant further attention before its use in children. ß

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Section: Discussionsupporting

confidence: 89%

The effect of rapamycin on bone growth in rabbits

Phornphutkul

Lee

Voigt

et al. 2009

Journal Orthopaedic Research

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“…5) in Ax 0 STZ rats, but it was elevated in a dose-dependent manner by corticosterone in both groups of STZ-injected animals. These results are consistent with previous reports (13,36), which suggested that the stimulatory effect of corticosterone on GH (7,17,40). Therefore, the failure of reduced IGF-I to cause a decrease in TEPW in the Ax nondiabetic rats (Table 1) is presumably due to the absence of corticosterone.…”

Section: Stzsupporting

confidence: 93%

Corticosterone Regulation of Insulin-Like Growth Factor I, IGF-Binding Proteins, and Growth in Streptozotocin-Induced Diabetic Rats

Rodgers

Strack²,

Dallman³

et al. 1995

Diabetes

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The experiments reported herein were conducted to determine how corticosterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and streptozotocin (STZ)-induced diabetic rats. Males were bilaterally adrenalectomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP concentrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IG-FBP-6 was detected in any of the treatment groups. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabetic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 were not significantly changed. Adrenalectomy had no affect on tibial growth or plasma IGFBP-1 in these animals. Plasma IGF-I, IGFBP-1 and -3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that did not receive corticosterone. Plasma IGFBP-4 was inversely related to the amount of STZ injected in these animals, and IGFBP-2 was elevated in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IGF-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increased in proportion with the dose of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Most glucocorticoid effects on endochondral bone growth appear to be due to direct regulation of chondrocytes, as opposed to generalized endocrine effects [11,12]. While effects of glucocorticoids on chondrocyte proliferation, differentiation and apoptosis as well as on vascular invasion of hypertrophic cartilage have been reported, the contributions of these effects to growth retardation and the molecular mechanisms involved are not completely understood [7,8,13].…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone stimulates expression of C-type Natriuretic Peptide in chondrocytes

Agoston

Baybayan

Beier

2006

BMC Musculoskelet Disord

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BackgroundGrowth of endochondral bones is regulated through the activity of cartilaginous growth plates. Disruption of the physiological patterns of chondrocyte proliferation and differentiation – such as in endocrine disorders or in many different genetic diseases (e.g. chondrodysplasias) – generally results in dwarfism and skeletal defects. For example, glucocorticoid administration in children inhibits endochondral bone growth, but the molecular targets of these hormones in chondrocytes remain largely unknown. In contrast, recent studies have shown that C-type Natriuretic Peptide (CNP) is an important anabolic regulator of cartilage growth, and loss-of-function mutations in the human CNP receptor gene cause dwarfism. We asked whether glucocorticoids could exert their activities by interfering with the expression of CNP or its downstream signaling components.MethodsPrimary mouse chondrocytes in monolayer where incubated with the synthetic glucocorticoid Dexamethasone (DEX) for 12 to 72 hours. Cell numbers were determined by counting, and real-time PCR was performed to examine regulation of genes in the CNP signaling pathway by DEX.ResultsWe show that DEX does influence expression of key genes in the CNP pathway. Most importantly, DEX significantly increases RNA expression of the gene encoding CNP itself (Nppc). In addition, DEX stimulates expression of Prkg2 (encoding cGMP-dependent protein kinase II) and Npr3 (natriuretic peptide decoy receptor) genes. Conversely, DEX was found to down-regulate the expression of the gene encoding its receptor, Nr3c1 (glucocorticoid receptor), as well as the Npr2 gene (encoding the CNP receptor).ConclusionOur data suggest that the growth-suppressive activities of DEX are not due to blockade of CNP signaling. This study reveals a novel, unanticipated relationship between glucocorticoid and CNP signaling and provides the first evidence that CNP expression in chondrocytes is regulated by endocrine factors.

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Catch-up growth after glucocorticoid excess: a mechanism intrinsic to the growth plate.

Cited by 106 publications

References 12 publications

The effect of rapamycin on bone growth in rabbits

The effect of rapamycin on bone growth in rabbits

Corticosterone Regulation of Insulin-Like Growth Factor I, IGF-Binding Proteins, and Growth in Streptozotocin-Induced Diabetic Rats

Dexamethasone stimulates expression of C-type Natriuretic Peptide in chondrocytes

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