Involvement of activin/BMP system in development of human pituitary gonadotropinomas and nonfunctioning adenomas

Takeda, Masaya; Otsuka, Fumio; Suzuki, Jirô; Kishida, Masayuki; Ogura, Toshio; Tamiya, Takashi; Makino, Hírofumi

doi:10.1016/s0006-291x(03)01052-0

Cited by 51 publications

(46 citation statements)

References 25 publications

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“…Subsequently, hot-start PCR was performed using MgCl 2 (1.5 mM), deoxynucleotide triphosphate (0.2 mM) and 2.5 U of Taq DNA polymerase (Invitrogen Corp.) under the conditions we previously reported. 17 PCR primer pairs were selected from different exons of the corresponding genes as follows: activin receptor-like kinase (ALK)-2, 639-661 and 1100-1121 (from GenBank accession #NM_007394); ALK-3, 426-445 and 916-935 (from NM_009758); BMP type II receptor, 13-32 and 515-534 (from NM_007561); MR, 2978-2999 and 3219-3240 (from M36074); BMP-4, 200-220 and 420-440 (from NM_007554); BMP-7, 418-438 and 684-704 (from X56906); and a house-keeping gene, ribosomal protein L19 (RPL19), 373-393 and 547-567 (from NM_009078). For the quantification of BMP-4, BMP-7, ALK-2, ALK-3, BMP type II receptor and MR mRNA levels, real-time PCR was performed using a LightCyclerFastStart DNA master SYBR Green I system (Roche Diagnostic Co., Tokyo, Japan) under the condition of annealing at 60-62 1C with 4mM MgCl 2 following the manufacturer's protocol.…”

Section: Rna Extraction Reverse Transcriptase Pcr and Quantitative Rmentioning

confidence: 99%

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

et al. 2011

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Recent studies have shown that bone morphogenetic proteins (BMPs), particularly BMP-7, have an inhibitory role in the development of various renal diseases. We previously reported antagonistic effects of BMPs on renal mesangial cell proliferation induced by aldosterone (Aldo) in vitro. In the present study, we investigated in vivo roles of BMPs in Aldo-induced renal glomerular injury. BALB/c mice aged 6 weeks were treated with Aldo injection (5 lg per day, intraperitoneally) and/or oral administration of high-salt (2%) water for 9 weeks. Systemic blood pressure, body weight, kidney weight and daily proteinuria were not significantly changed by Aldo and/or high-salt treatment. However, renal histological examination revealed increases in glomerular cellularity and glomerular diameter in the groups treated with Aldo injection and high-salt administration. Immunohistochemistry demonstrated expression of BMP-4 and -7 in the glomerular mesangial region. Aldo causes renal glomerular damage by stimulating mesangial cell proliferation and increasing extracellular matrix via the mineralocorticoid receptor (MR). MR messenger RNA (mRNA) expression in the renal cortex was transiently increased by 3-week treatment with Aldo and high-salt intake, but was decreased by 9-week treatment. Furthermore, the expression levels of BMP-4 and -7 mRNA were enhanced in the renal cortex treated with Aldo and high-salt administration. These findings suggest that the renal BMP system is activated by Aldo under the condition of high-salt exposure, which may have a key role in antagonizing glomerular damage in vivo.

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Section: Rna Extraction Reverse Transcriptase Pcr and Quantitative Rmentioning

confidence: 99%

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

et al. 2011

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“…PCR primer pairs for human BMP receptors, Smads and a house-keeping gene, ribosomal protein-L19, were selected from different exons of the corresponding genes to discriminate PCR products that might arise from possible chromosome DNA contaminants, as reported earlier. 25 For AT1R, ET type-A (ETAR) and type-B receptors (ETBR), mineralocorticoid receptor (MR), noggin, activin receptor-like kinase (ALK)-1, Id-1 and 11b-hydroxysteroid dehydrogenase type 2 (11bHSD2), the following sequences were used: AT1R, 34-53 and 376-395 from GenBank accession number M93394; ETAR, 275-295 and 483-503 from L06622; ETBR, 931-951 and 1172-1192 from S44866; MR, 2730-2751 and 2971-2992 from M16801; noggin, 541-561 and 750-770 from NM_005450; ALK-1, 1160-1180 and 1501-1521 from NM_001077401; Id-1, 211-230 and 350-369 from X77956; and 11bHSD2, 611-631 and 882-902 from U27317. The extracted RNA (1 mg) was subjected to a RT reaction using First-Strand cDNA Synthesis System (Invitrogen) with random hexamers (2 ng ml À1 ), reverse transcriptase (200 U) and deoxynucleotide triphosphate (dNTP; 0.5 mM) at 421C for 50 min and then at 701C for 10 min.…”

Section: Total Cellular Rna Extraction and Reverse Transcriptase-pcrmentioning

confidence: 99%

“…Hot-start PCR was then performed using MgCl 2 (1.5 mM), dNTP (0.2 mM) and 2.5 U of Taq DNA polymerase (Invitrogen) under the conditions as we have reported previously. 25 Aliquots of the PCR products were electrophoresed on 1.5% agarose gels, visualized after ethidium bromide staining, photographed and scanned.…”

Section: Total Cellular Rna Extraction and Reverse Transcriptase-pcrmentioning

confidence: 99%

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

et al. 2010

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Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11bHSD2 (11b-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

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“…Interestingly, when we sub-classified the group into LH/FSH adenomas or null cell adenomas based on immunocytochemical staining, there was no significant difference in the serum LH:FSH ratios between the groups, suggesting that the preferential secretion of FSH in vivo occurs irrespectively of immunocytochemical findings in surgically removed tissue. Takeda et al (17) found exclusively higher FSH:LH ratios (i.e. lower LH:FSH ratios) in a subset of five FSHomas, compared with other pituitary adenomas, including NFPAs, PRLomas and GHomas.…”

Section: Discussionmentioning

confidence: 97%

“…At the pituitary level, activin acts in a local manner to stimulate FSH expression and secretion and has an antiproliferative effect, with these actions being blocked by follistatin and inhibin (21). A positive correlation has been demonstrated in NFPAs between activin and FSH by two groups (17,18). Other studies have shown that the antiproliferative effect of activin may be lost in some gonadotrophinomas (22).…”

Section: Discussionmentioning

confidence: 99%

FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas

Hanson

Aylwin²,

Monson³

et al. 2005

eur j endocrinol

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Objective: Non-functioning pituitary adenomas (NFPAs) are characterised by the lack of symptoms of hormone hypersecretory syndromes but in vitro studies have demonstrated that tumour cells may stain for gonadotrophins and/or their a-or b-subunits. In this study, we aimed to examine the pattern of secretion of LH and FSH from a series of pituitary adenomas cultured in vitro and where data were available to relate the results to pre-operative serum gonadotrophin levels. Methods: The in vitro secretion of LH and FSH was measured from 46 cultured NFPAs and compared with pre-operative serum gonadotrophin levels in 38 patients. Peri-tumorous 'normal' pituitary cell cultures from 20 additional pituitary tumour patients were used for comparison with the NFPA group. Results: A median pre-operative LH:FSH ratio of 0.33:1 was found in 38 patients with NFPAs. Preferential secretion of FSH was also documented from media of 46 NFPAs cultured in vitro with a median LH:FSH ratio of 0.32:1. A significant correlation (r ¼ 0.43, P , 0.01) was observed between serum and media levels of FSH but not LH. Peri-tumorous 'normal' pituitary cells released LH and FSH in a reversed ratio (median LH:FSH ratio ¼ 3.6:1, P , 0.01 compared with NFPAs). Conclusions: This study has evaluated pre-operative serum gonadotrophin levels and in vitro release of hormones in cultures of surgically removed tissue from patients with NFPAs. The data suggest preferential secretion of FSH occurs both in vitro and in vivo. By demonstrating that NFPAs cultured in vitro reflect the in vivo situation of preferential secretion of FSH, it may be possible in future to perform functional studies using this system to elucidate the cellular and molecular mechanisms involved in the development of an imbalance in gonadotroph cells preferentially overproducing FSH in NFPAs.

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Involvement of activin/BMP system in development of human pituitary gonadotropinomas and nonfunctioning adenomas

Cited by 51 publications

References 25 publications

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas

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