Androgen receptor knockout and knock-in mouse models

Kerkhofs, Stefanie; Denayer, Sarah; Haelens, Anna; Claessens, Frank

doi:10.1677/jme-08-0122

Cited by 70 publications

(48 citation statements)

References 62 publications

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“…In line with these observations, the embryonic lethal phenotypes observed in the HSD17BKO2, 7 and 12 mice do not mimic the phenotype alterations observed in mice deficient in estrogen receptor-a (Esr1), estrogen receptor-b (Esr2) and AR (Matsumoto et al 2003, Hewitt et al 2005, Zhao et al 2008, Kerkhofs et al 2009), or those over-exposed to sex steroids. This further points towards other enzymatic activities associated with these HSD17B enzymes.…”

Section: Knockout Micementioning

confidence: 79%

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

Saloniemi

Jokela²,

Strauss³

et al. 2011

Journal of Endocrinology

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Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17b) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17b-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studies in vitro and in vivo are to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.

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Section: Knockout Micementioning

confidence: 79%

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

Saloniemi

Jokela²,

Strauss³

et al. 2011

Journal of Endocrinology

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“…Another strategy to assess hormonal effects genetically is the use of animal models with sex-hormone receptor knockouts. (29,30).…”

Section: Preclinical Researchmentioning

confidence: 99%

Studying both sexes: a guiding principle for biomedicine

2015

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In May 2014, the U.S. National Institutes of Health (NIH) announced that it will ensure that investigators account for sex as a biological variable (SABV) in NIHfunded preclinical research as part of the agency's rigor and transparency initiative. Herein, I describe in more detail the rationale behind the SABV policy component and provide additional detail about policy goals. In short, studying both sexes is a guiding principle in biomedical research that will expand knowledge toward turning discovery into health. NIH expects that considering SABV in preclinical research will help to build a knowledge base that better informs the design of clinical research and trials in humans. Integrating the practice of studying both sexes in preclinical research will, over time, expand our currently incomplete knowledge base that plays a critical role in informing the development of sexand gender-appropriate medical care for women and men.-Clayton, J. A. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30, 519-524 (2016). www.fasebj.org

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“…For example, the androgen receptors (ARs) present in SCs play a critical role in this association and thus, in the maintenance of spermatogenesis. Although it is a controversial matter if germ cells express or not ARs [43], it has been shown that mice with a germ cell selective knockout of the AR present normal spermatogenesis [44]. But, interestingly, when ARs were ablated in SCs, the germ cell development stopped at the spermatocyte [45,46] or early spermatid stages [47], illustrating that SCs are the primary site of action for ARsmediated effects and that these processes are essential for germ cell development.…”

Section: General Aspects Of Sertoli-germ Cell Associationmentioning

confidence: 99%

Metabolic Cooperation in Testis as a Pharmacological Target: From Disease to Contraception

Alves¹,

Dias²,

Silva³

et al. 2015

CMP

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Abstract:The development of a "male pill" to control fertility is still a major challenge. Although women have several options to play an active role in the couple family planning, men are very limited in terms of contraceptive methods. Several approaches have been proposed to develop a male contraceptive and can be divided in two major groups: hormonal and non-hormonal methods. Within the testis, the somatic Sertoli cell (SC) is known as the "nurse cell" since it provides the physical and nutritional support for the developing germ cells. Moreover, adjacent SCs form the Sertoli/blood testis barrier (BTB), which divides the seminiferous epithelium into the basal and the apical compartments, controlling the passage of substances to the site where germ cells develop. Among the several functions of SC, its metabolism and the production of lactate, acetate and other metabolic factors are essential for the normal occurrence of spermatogenesis. In the last years, several works have highlighted that the metabolic cooperation established between SCs and developing germ cells is compromised in several diseases associated with male subfertility/infertility. Notably, several metabolismassociated proteins are specifically expressed in the testis. Thus, there are several evidences illustrating that the control of male fertility can be achieved by targeting testicular cells metabolism. Herein, we discuss the metabolic cooperation in testis as a potential pharmacological target to counteract subfertility/infertility promoted by several diseases, particularly metabolic diseases. We also discuss how it can contribute to the development of a male contraceptive.

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Androgen receptor knockout and knock-in mouse models

Cited by 70 publications

References 62 publications

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

Studying both sexes: a guiding principle for biomedicine

Metabolic Cooperation in Testis as a Pharmacological Target: From Disease to Contraception

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