The Osteogenic Transcription Factor Runx2 Controls Genes Involved in Sterol/Steroid Metabolism, Including Cyp11a1 in Osteoblasts

Teplyuk, Nadiya M.; Zhang, Ying; Lou, Yang; Hawse, John R.; Hassan, Mohammad Q.; Teplyuk, Viktor I.; Pratap, Jitesh; Galindo, Mario; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.; Wijnen, André J. van

doi:10.1210/me.2008-0270

Cited by 48 publications

(33 citation statements)

References 77 publications

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“…This enzyme is a mitochondrial membrane-bound protein mainly expressed in the adrenal cortex, ovary, testis and placenta (Payne & Hales 2004). Moreover, Teplyuk et al (2009) detected the expression of one N-terminally truncated CYP11A1 isoform in mouse and human osteoblastic cell lines, regulated by RUNX2. This 32-kDa isoform was localized in cytoplasm and nucleus but not in the mitochondria; its function remains unknown.…”

Section: Discussionmentioning

confidence: 99%

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Rodríguez-Sanz

Garcia-Giralt

Prieto-Alhambra

et al. 2015

Journal of Molecular Endocrinology

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Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P!0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss. Journal of Molecular EndocrinologyResearch M RODRI´GUEZ-SANZ and others CYP11A1 is associated with AI-related bone loss 55:1 69-79http://jme.endocrinology-journals.org Ñ 2015 Society for Endocrinology DOI: 10.1530/JME-15-0079Printed in Great BritainPublished by Bioscientifica Ltd. IntroductionAromatase inhibitors (AIs) are commonly used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. Although AIs are generally well tolerated with few serious adverse events, a number of musculoskeletal side effects affecting quality of life have been noted and often lead to discontinuation of therapy (Eastell et al. 2006, Henry et al. 2008.The most common side effects reported with AIs are exacerbation of menopausal symptoms as a result of low estrogen levels; these include pain syndromes, bone loss and associated fracture , Laroche et al. 2014. Several prospective studies and clinical trials have noted the need for assessment and treatment of these musculoskeletal adverse events (Reid et al. 2008, Brufsky et al. 2009, Servitja et al. 2012. In particular, bone mineral density (BMD) reduction and fracture incidence associated with AI therapy can be significantly reduced by oral bisphosphonates (BP) treatment (Bouvard et al. 2014).We are currently conducting a prospective, nonselected, observational, clinical cohort study (BarcelonaAromatase induced bone loss in early breast cancer (B-ABLE...

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Section: Discussionmentioning

confidence: 99%

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Rodríguez-Sanz

Garcia-Giralt

Prieto-Alhambra

et al. 2015

Journal of Molecular Endocrinology

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“…In contrast to ox-A1AT, patients with high ox-A1AT expression had shorter survival than those with low expression. It has been known that RUNX2 controls genes involved in sterol/steroid metabolism, including Cyp11a1, Cyp39a1, Cyp51, Lss, and Dhcr7, discovered in murine osteoprogenitor cells (Teplyuk et al, 2009). In addition, the tumor suppression property of RUNX2 has been reported in breast cancer cell lines in blocking the effect of estradiol, resulting in inhibiting tumor growth (Chimge et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

Khenjanta

Thanan²,

Jusakul³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

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“…Several studies have examined Runx2-responsive genes in osteoprogenitors (Teplyuk et al . 2008, 2009 a , 2009 b ), in mouse embryonic fibroblasts (MEFs; Wotton et al . 2008, Kilbey et al .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation

Emons¹,

Dutilh²,

Decker

et al. 2011

Journal of Endocrinology

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In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P = 0.002), height of the individual zones (P < 0.001), and an increase in intercolumnar space (P < 0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P < 0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.

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The Osteogenic Transcription Factor Runx2 Controls Genes Involved in Sterol/Steroid Metabolism, Including Cyp11a1 in Osteoblasts

Cited by 48 publications

References 77 publications

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss

Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation

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