Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss

Lehmann, Juliane; Thiele, Stefanie; Baschant, Ulrike; Rachner, Tilman D.; Niehrs, Christof; Hofbauer, Lorenz C.; Rauner, Martina

doi:10.1016/j.isci.2021.102224

Cited by 20 publications

(11 citation statements)

References 84 publications

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“…In addition, miR-1278 was positively associated with sclerostin and Dkk1, which are inhibitors of the WNT signaling pathway. These associations are in concordance with previous studies on the association between inhibitors of the WNT signaling pathway and estrogen status (40)(41)(42)(43)(44). The Wnt/ b-catenin pathway activation enhances bone mass not only by stimulating osteoblastogenesis but, at least to some extent, also by inhibiting osteoclastogenesis as well (44).…”

Section: Discussionsupporting

confidence: 92%

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism

et al. 2022

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ObjectiveOsteoporosis is associated with an impaired balance between bone resorption and formation, which in turn leads to bone loss and fractures. Many recent studies have underlined the regulatory role of microRNAs (miRNAs) in bone remodeling processes and their potential as biomarkers of osteoporosis. The purpose of this study was to prospectively examine the association of circulating miRNAs and bone biomarkers with estrogen status in women before and after oophorectomy, as well as in oophorectomized women on estrogen therapy.MethodsIn this prospective study, we included 11 women before oophorectomy and hysterectomy and at 201 ± 24 days after the surgery. Another 11 women were evaluated 508 ± 127 days after oophorectomy and hysterectomy and after an additional 203 ± 71 days of estradiol treatment. Serum miRNAs were profiled by sequencing. Estrogen status and biomarkers of bone metabolism were quantified. Bone mineral density was assessed in the lumbar spine.ResultsOur analysis revealed 17 miRNAs associated with estrogen levels. Of those miRNAs that were upregulated with estrogen deficiency and downregulated after estrogen therapy, miR-422a correlated with serum beta-carboxy-terminal type I collagen crosslinks (β-CTX) and procollagen 1 N-terminal propeptide (P1NP); and miR-1278 correlated with serum β-CTX, P1NP, osteocalcin, sclerostin, and Dickkopf-1(Dkk1). In contrast, we found an inverse association of miR-24-1-5p with estrogen status and a negative correlation with serum β-CTX, P1NP, osteoprotegerin, and sclerostin levels.ConclusionThe reported miRNAs associated with estrogen status and bone metabolism could be potential biomarkers of bone pathophysiology and would facilitate studies on the prevention of postmenopausal osteoporosis. Our findings require validation in an extended cohort.

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Section: Discussionsupporting

confidence: 92%

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism

et al. 2022

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“…Among these, IGF1 activates phosphoinositide 3-kinase (PI3K)/Akt mammalian target of rapamycin (mTOR) pathway, with subsequent breast cancer cell growth, proliferation, and migration into the bone [17,61,62]. Osteoblasts can also be regulated by metastatic tumor cell-derived factors including endothelin 1 (ET1), dickkopf 1 (DKK1), and the Wnt signaling cascade [36,[63][64][65][66]. While Wnt promotes osteoblast differentiation, its activity can be inhibited by DKK1, which is an antagonist in this cascade.…”

Section: Biological Mechanisms Of Bone Metastasismentioning

confidence: 99%

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

Venetis

Piciotti

Sajjadi

et al. 2021

Cells

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Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient’s survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients’ survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic.

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“…The expression of DKK1 in CD4 + and CD8 + T cells was increased in ovariectomized mice. No literature has reported the correlation between LINGO2 and GTF2H4 and estrogen [ 63 ]. Our findings suggested that the estrogen signaling pathway might affect the progression and prognosis of LUAD by regulating the expression of these four genes.…”

Section: Discussionmentioning

confidence: 99%

Immune characteristics analysis and construction of a four-gene prognostic signature for lung adenocarcinoma based on estrogen reactivity

Wang,

Yu,

Chen

et al. 2023

BMC Cancer

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Lung adenocarcinoma (LUAD) is a common type of malignant tumor with poor prognosis and high mortality. In our previous studies, we found that estrogen is an important risk factor for LUAD, and different estrogen statuses can predict different prognoses. Therefore, in this study, we constructed a prognostic signature related to estrogen reactivity to determine the relationship between different estrogen reactivities and prognosis. We downloaded the LUAD dataset from The Cancer Genome Atlas (TCGA) database, calculated the estrogen reactivity of each sample, and divided them into a high-estrogen reactivity group and a low-estrogen reactivity group. The difference in overall survival between the groups was significant. We also analyzed the status of immune cell infiltration and immune checkpoint expression between the groups. We analyzed the differential gene expression between the groups and screened four key prognostic factors by the least absolute shrinkage and selection operator (LASSO) regression and univariable and multivariable Cox regression. Based on the four genes, a risk signature was established. To a certain extent, the receiver operating characteristic (ROC) curve showed the predictive ability of the risk signature, which was further verified using the GSE31210 dataset. We also determined the role of estrogen in LUAD using an orthotopic mouse model. Additionally, we developed a predictive nomogram combining the risk signature with other clinical characteristics. In conclusion, our four-gene prognostic signature based on estrogen reactivity had prognostic value and can provide new insights into the development of treatment strategies for LUAD.

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Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss

Cited by 20 publications

References 84 publications

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

Immune characteristics analysis and construction of a four-gene prognostic signature for lung adenocarcinoma based on estrogen reactivity

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