Bone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly... Show moreBone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context.We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO-and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples.In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplemen-tation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis. Show less
STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe... Show moreSTAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old female subject who had severe postnatal growth impairment, biochemistries typical of GHI, an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease. Marked elevation of serum prolactin and pathologically diagnosed eczema were evident. In reconstitution studies, the STAT5B p.(Asp485Thrfs*29) was expressed although expression was reduced compared to wild-type STAT5B and a previously identified STAT5B p.(Gln368Profs*9) variant. Both truncated STAT5B peptides could not be activated by GH, nor mobilize to the nucleus. We conclude that an intact, func-tional, STAT5B is essential for normal GH-mediated growth, while expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency. Show less
The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through... Show moreThe insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth. Show less
Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the... Show moreAdrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the development of atherosclerotic cardiovascular disease. Here we review preclinical and clinical findings regarding the relation between changes in plasma glucocorticoid levels and the atherosclerosis extent. It appears that, although the altered glucocorticoid function can in most cases be restored in the different patient groups, current therapies do not necessarily reverse the associated risk for atherosclerotic cardiovascular disease. In our opinion much attention should therefore be given to the development of a Cushing's disease mouse model that can (1) effectively replicate the effect of hypercortisolemia on atherosclerosis outcome observed in humans and (2) be used to investigate, in a preclinical setting, the relative impact on atherosclerosis susceptibility of already available (e.g. metyrapone) and potentially novel (i.e. SR-BI activity modulators) therapeutic agents that target the adrenal glucocorticoid output. Show less
The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both... Show moreThe balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor alpha. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Show less
