記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ebiomedicine  

Background: Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear. Methods: ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues. Findings: Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis. Interpretation: This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS. Funding: JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JST A-STEP, JST-Moonshot, and Ono Medical Research Foundation.

DOI： 10.1016/j.ebiom.2023.104733

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Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Reports  

Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = −0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η² = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. Conclusion: In endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

DOI： 10.1016/j.bonr.2022.101610

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

CONTEXT: Autonomous cortisol secretion (ACS) is a common cause of endogenous glucocorticoid-induced osteoporosis. Cortisol excess alone, however, does not fully explain altered bone status, and other steroid hormone changes, including androgen deficiency, may contribute. ACS is also associated with an inflammatory state, which may relate to changes in bone status and steroid profiles. PURPOSE: To investigate whether inflammatory markers are associated with bone status and steroid profiles in ACS and explore their potential mediating role. METHODS: Inflammatory markers and bone status were assessed in 106 patients with ACS and 95 with non-functioning adrenal tumors (NFAT). Of these, plasma steroid profiles were measured by liquid chromatography-tandem mass spectrometry in 64 patients with ACS and 77 with NFAT. Analyses examining associations between inflammatory markers and bone status or steroid profiles were stratified by sex and menopausal status. RESULTS: ACS showed higher systemic immune-inflammation index (SII) and lower prognostic nutritional index (PNI) than NFAT. In premenopausal women with ACS, SII negatively correlated with trabecular bone score (TBS) (r = -0.38), while PNI positively correlated with TBS (r = 0.58). Androsterone-glucuronide (AND-G), an androgen metabolite, was negatively correlated with SII (r = -0.59) and positively with PNI (r = 0.74). SHapley Additive exPlanations and Bayesian Kernel Machine Regression identified AND-G as the strongest contributor to PNI. PNI mediated 59.9% of the association between AND-G and TBS. MAIN CONCLUSIONS: Inflammatory markers were associated with deteriorated bone quality, especially in premenopausal women with ACS. Androgen deficiency was associated with inflammation, partially contributing to bone deterioration.

DOI： 10.1210/clinem/dgaf632

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/HYPERTENSIONAHA.125.24825

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Plos One  

The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods.

DOI： 10.1371/journal.pone.0296006

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記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語