Loss of androgen receptor promotes adipogenesis but suppresses osteogenesis in bone marrow stromal cells

Huang, Chiung‐Kuei; Lai, Kuo-Pao; Luo, Jie; Tsai, Ming-Yi; Kang, Hong-Yo; Chen, Yuhchyau; Lee, Soo Ok; Chang, Chawnshang

doi:10.1016/j.scr.2013.06.001

Cited by 21 publications

(21 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This lineage restriction is indicative of a more progenitor‐like phenotype being dominant in primary prostate stromal cultures derived from normal tissue as opposed to canonical MSCs, which are typically associated with a broader differentiation potential. Preliminary evidence suggests this lineage restriction is a functional consequence of TGF‐β and AR signaling in the prostate, which drives MSCs down the smooth muscle lineage; a concept with strong support in the literature . Of note, the greatest number of overall PDs and fastest PDTs were observed in cultures grown in media containing low TGF‐β concentrations.…”

Section: Discussionmentioning

confidence: 84%

Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures

2016

View full text Add to dashboard Cite

BACKGROUND Carcinoma-associated fibroblasts (CAFs) are a dominant component of the tumor microenvironment with pro-tumorigenic properties. Despite this knowledge, their physiologic origins remain poorly understood. Mesenchymal stem cells (MSCs) can be recruited from the bone marrow to areas of tissue damage and inflammation, including prostate cancer. MSCs can generate and have many overlapping properties with CAFs in preclinical models. METHODS Multiparameter flow cytometry and multipotent differentiation assays used to define MSCs in primary prostate stromal cultures derived from young (>25 yrs) organ donors and prostate cancer patients compared with bone marrow-derived stromal cultures. Population doubling times, population doublings, cell size, and differentiation potential determined under multiple culture conditions, including normoxia, hypoxia, and a variety of media. TGF-β measured by ELISA. RESULTS MSCs and stromal progenitors are not only present in normal and malignant prostate tissue, but are quickly selected for in primary stromal cultures derived from these tissues; becoming the dominant population within just a few passages. Growth potential inversely associated with TGF-β concentrations. All conditions generated populations with an average cell diameter >15 μm. All cultures tested had the ability to undergo osteogenic and chondrogenic differentiation, but unlike bone marrow-derived MSCs, primary stromal cultures derived from normal prostate tissue lack adipogenic differentiation potential. In contrast, a subset of stromal cultures derived from prostate cancer patients retain the ability to differentiate into adipocytes; a property that is significantly suppressed under hypoxic conditions in both bone marrow- and prostate-derived MSCs. CONCLUSIONS Primary prostate stromal cultures are highly enriched in cells with an MSC or stromal progenitor phenotype. The use of primary cultures such as these to study CAFs raises interesting implications when considering their overlapping properties. The lack of adipogenesis in stromal cultures derived from normal prostates suggests they have a lineage-restricted progenitor phenotype. The retention of adipogenic differentiation in cultures from a subset of prostate cancer patients suggests the active recruitment of less committed progenitors or MSCs from the bone marrow as a function of disease progression. This recruitment can potentially be exploited for prognostic purposes or a cell-based platform for the systemic delivery of cytotoxic agents to sites of prostate cancer.

show abstract

Section: Discussionmentioning

confidence: 84%

Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures

2016

View full text Add to dashboard Cite

show abstract

“…AR level is negatively correlated with adipogenesis in BMSCs18. Given the upregulation in AR expression and inhibition of adipogenesis induced by AMPK α2 as compared to AMPK α1 overexpression, a role for AR in adipogenesis was examined by infecting LV-AMPKα1 and LV-AMPKα2 3T3-L1 cells with a virus expressing AR and a siRNA against AR respectively, and inducing adipogenic differentiation.…”

Section: Resultsmentioning

confidence: 99%

Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis

Wang

Han

Yang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

The endocrine role of the skeleton-which is impaired in human diseases including osteoporosis, obesity and diabetes-has been highlighted previously. In these diseases, the role of AMPK, a sensor and regulator of energy metabolism, is of biological and clinical importance. Since AMPK’s main catalytic subunit α has two isoforms, it is unclear whether functional differences between them exist in the skeletal system. The current study overexpressed AMPKα1 and α2 in MC3T3-E1 cells, primary osteoblasts and mouse BMSCs by lentiviral transduction. Cells overexpressing AMPKα2 showed higher osteogenesis potential than AMPKα1, wherein androgen receptor (AR) and osteoactivin played important roles. RANKL and M-CSF were secreted at lower levels from cells overexpressing α2 than α1, resulting in decreased osteoblast-associated osteoclastogenesis. Adipogenesis was inhibited to a greater degree in 3T3-L1 cells overexpressing α2 than α1, which was modulated by AR. An abnormal downregulation of AMPKα2 was observed in human BMSCs exhibiting the fibrous dysplasia (FD) phenotype. Overexpression of AMPKα2 in these cells rescued the defect in osteogenesis, suggesting that AMPKα2 plays a role in FD pathogenesis. These findings highlight functional differences between AMPKα1 and α2, and provide a basis for investigating the molecular mechanisms of diseases associated with impaired functioning of the skeletal system.

show abstract

“…Binding of testosterone and its metabolite, 5α‐dihydroxytestosterone (DHT), to AR would induce AR dimerization, translocation into nuclei, and binding to the AR response elements (AREs) to regulate gene expression . The expression of AR has been detected in various tissues other than those of the reproductive system . Deficiency of AR causes several diseases and AR is one of the key determinants in prostate cancer (PCa).…”

Section: Introductionmentioning

confidence: 99%

Concise Review: Androgen Receptor Differential Roles in Stem/Progenitor Cells Including Prostate, Embryonic, Stromal, and Hematopoietic Lineages

et al. 2014

Self Cite

View full text Add to dashboard Cite

Stem/progenitor (S/P) cells are special types of cells that have the ability to generate tissues throughout their entire lifetime and play key roles in the developmental process. Androgen and the androgen receptor (AR) signals are the critical determinants in male gender development, suggesting that androgen and AR signals might modulate the behavior of S/P cells. In this review, we summarize the AR effects on the behavior of S/P cells, including self-renewal, proliferation, apoptosis, and differentiation in normal S/P cells, as well as proliferation, invasion, and self-renewal in prostate cancer S/P cells. AR plays a protective role in the oxidative stress-induced apoptosis in embryonic stem cells. AR inhibits the self-renewal of embryonic stem cells, bone marrow stromal cells, and prostate S/P cells, but promotes their differentiation except for adipogenesis. However, AR promotes the proliferation of hematopoietic S/P cells and stimulates hematopoietic lineage differentiation. In prostate cancer S/P cells, AR suppresses their self-renewal, metastasis, and invasion. Together, AR differentially influences the characteristics of normal S/P cells and prostate cancer S/P cells, and targeting AR might improve S/P cell transplantation therapy, especially in embryonic stem cells and bone marrow stromal cells.

show abstract

Loss of androgen receptor promotes adipogenesis but suppresses osteogenesis in bone marrow stromal cells

Cited by 21 publications

References 67 publications

Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures

Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures

Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis

Concise Review: Androgen Receptor Differential Roles in Stem/Progenitor Cells Including Prostate, Embryonic, Stromal, and Hematopoietic Lineages

Contact Info

Product

Resources

About