Androgen receptor activation integrates complex transcriptional effects in osteoblasts, involving the growth factors TGF-β and IGF-I, and transcription factor C/EBPδ

McCarthy, Thomas L.; Centrella, Michael

doi:10.1016/j.gene.2015.07.037

Cited by 10 publications

(3 citation statements)

References 75 publications

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“…Increased serum IGF-1 plays a critical role in higher osteoarthritis incidence [ 61 ]. PGE2 has a strong effect on IGF-1 gene promoter activity, and increased IGF-1 intensively results in the abnormal formation and altered architecture of subchondral bone [ 62 , 63 ]. Increased IGF-1 and PGE2 proteins in osteoarthritic subchondral bone also downregulate the PTH receptor expression of osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

Sun

Zhang

Ding

et al. 2022

Cells

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Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone’s abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

Sun

Zhang

Ding

et al. 2022

Cells

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“…In the bone microenvironment, there are AR-positive osteoblasts ( McCarthy & Centrella 2015 , Villagran et al 2015 ), where androgens regulate bone reabsorption and mass ( Kawano et al 2003 ). Here, AR also regulates TGFB secretion, which may have bearing on how hospitable cancer cells find the bone.…”

Section: Coregulatorsmentioning

confidence: 99%

Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer

2022

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Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate resistant prostate cancer cells (CRPC) and treatment naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states.

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“…The abnormal hormonal milieu in PCOS can have implications on bone metabolism, bone mineral density (BMD), and the peak bone mass (PBM) attained. Hyperandrogenemia could have a positive effect on BMD through its direct actions on receptors present on osteoblasts [12] or indirectly by its aromatization to estrogens in adipose tissue [13]. Increased insulin levels have a stimulating effect on osteoblasts [14] besides increasing the levels of bioavailable sex steroids through decreasing sex hormone binding globulin (SHBG) levels [15,16].…”

Section: Introductionmentioning

confidence: 99%

Bone Mineral Density is Unaltered in Women with Polycystic Ovary Syndrome

et al. 2018

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Context The effects of endocrine aberrations associated with polycystic ovary syndrome (PCOS) on bone mineral density (BMD) in young women is a matter of debate. Objectives To compare BMD in young women with PCOS to age and body mass index (BMI) matched controls and to elucidate its correlation to BMI, insulin resistance and serum testosterone. Design and Methods We recruited 60 women with PCOS aged 14-24 years, diagnosed based on Rotterdam 2003 criteria, and 58 age matched controls. BMD was measured by dual energy X-ray absorptiometry. In addition, these subjects underwent biochemical and hormonal analysis including oral glucose tolerance test, calculation of Homeostatic Model Assessment–Insulin Resistance Index, measurement of serum thyroxine, thyrotropin, prolactin, total testosterone, dehydroepiandrosterone sulfate, follicular phase luteinizing hormone and follicle stimulating hormone. Results There was no difference of BMD between women with PCOS and control women (1.103±0.08 vs 1.126±0.083 g/cm2; p=0.122). In subgroup analysis based on BMI, BMD in obese women with PCOS was significantly higher than their overweight and lean counterparts at lumbar spine (p<0.001), neck of femur (p=0.005) and total hip (p<0.001). BMD was not different at any site between oligomenorrheic and non-oligomenorrheic women with PCOS. It positively correlated with BMI, waist and hip circumference in women with PCOS. No correlation was found with HOMA-IR or Testosterone. Conclusions BMI is the most important determinant of BMD in women with PCOS. BMD is not different between healthy young women and those with PCOS.

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Androgen receptor activation integrates complex transcriptional effects in osteoblasts, involving the growth factors TGF-β and IGF-I, and transcription factor C/EBPδ

Cited by 10 publications

References 75 publications

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer

Bone Mineral Density is Unaltered in Women with Polycystic Ovary Syndrome

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