Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

Abstract

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases.

Figure 1. The summary of androgen-AR roles in the development of 4 immune cell types including neutrophils, macrophages, T lymphocytes, and B lymphocytes.

This cartoon describes the roles of androgen/AR signaling during the development of these immune cell types as deduced from phenotypic observations of the ARKO mice indicated in the figure. The potential AR downstream regulatory molecules or mechanisms in these 4 immune cell types are also illustrated.

Figure 2. AR roles in metabolic syndrome and cardiovascular diseases (CADs).

Total ARKO (T-ARKO) mice displayed a greater extent of metabolic abnormalities including obesity, dyslipidemia, insulin resistance, and leptin resistance compared to Wt mice. The AR roles in various cell types for development of these metabolic abnormalities are deduced from the phenotype observations in neuron-specific ARKO (N-ARKO), hypothalamus-specific ARKO (Hyp-ARKO), hepatocyte-specific ARKO (Hep-ARKO), and adipocyte-specific ARKO (A-ARKO) mice. In CADs, T-ARKO mice have increased atherosclerosis plaque formation, but completely abolished aneurysm development. The AR roles in different cell types for CADs are deduced from observations in myeloid cell-specific ARKO (Myl-ARKO), smooth muscle cell-specific ARKO (SM-ARKO), and endothelial cell-specific ARKO (End-ARKO) mice. An up arrow indicates increase, whereas a down arrow denotes decrease in a metabolic abnormality or CAD symptom compared to Wt mice. The minus sign indicates no significant difference was observed between the specific ARKO and Wt mice.