The Dual Effector Theory

Ohlsson, Claes; Lindahl, Anders; Isgaard, Jörgen; Nilsson, Anders; Isaksson, Olle

doi:10.1002/cphy.cp070516

Cited by 2 publications

(2 citation statements)

References 153 publications

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“…Although liverderived IGF-I is the main determinant of systemic IGF-I levels, it appears that locally derived IGF-I is probably more important for postnatal growth. 21 Indeed, it is likely that GH and IGF-I have both dual and overlapping functions on chondrocytes, as both GHR and IGF-I mutant mice show reduced growth, which is more severe in double GHR/IGF-I mutants. 22 It is not clear whether GH mediates any IGF-I-independent effects on chondrocytes, because studies to date have largely been inconclusive.…”

Section: Discussionmentioning

confidence: 99%

Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease–related growth retardation

Troib

Landau

Kachko

et al. 2013

Kidney International

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Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression.

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Section: Discussionmentioning

confidence: 99%

Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease–related growth retardation

Troib

Landau

Kachko

et al. 2013

Kidney International

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“…Liver is the main organ that contributes to the blood circulating IGF-1 pool [27, 28, 59]; with IGF-1 playing an important role in bone physiology [25, 60, 61]. Taking into consideration that liver functions are compromised by psychosine-induced inflammation in twi animals [29], it was not surprising that mRNA expression and protein levels of IGF-1 were found to be down regulated in the liver of twi mice, supporting the drastic decrease in IGF-1 plasma levels observed in those mice.…”

Section: Discussionmentioning

confidence: 99%

Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease

Contreras

Ries

Shanmugarajan

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.

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The Dual Effector Theory

Cited by 2 publications

References 153 publications

Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease–related growth retardation

Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease–related growth retardation

Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease

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