Abstract
Proliferation and differentiation of adult Leydig cells are mainly completed in puberty. In many studies, apart from normal postnatal development process, it is widely indicated that, through administrating EDS, Leydig cell population is eliminated and regenerated. It is believed that osteocalcin released from osteoblasts, which is responsible for modulating bone metabolism, induces testosterone production in Leydig cells, independent of the HPG axis. In addition, INSL3 produced by Leydig cells, such as testosterone, plays a critical role in bone metabolism and is known to reflect the development process and functional capacities of Leydig cells. This study is aimed at investigating OC-mediated testosterone regulation and INSL3 synthesis during differentiation of adult Leydig cells that are independent of LH. For this purpose, male rats were divided into 2 groups: prepubertal normal rats and adult EDS-injected rats. Each group was divided into 4 subgroups in which GnRH antagonist or OC was applied. After adult Leydig cells completed their development, testicular tissue samples obtained from the sacrificed rats were examined by light-electron microscopic, immunohistochemical, and biochemical methods. Slight upregulation in 3βHSD, INSL3, and GPRC6A expressions along with the increase in serum testosterone levels was observed in groups treated with osteocalcin against GnRH antagonist. In addition, biochemical and microscopic findings in osteocalcin treated groups were similar to those in control groups. While there was no significant difference in the number of Leydig cells reported, the presence of a significant upregulation in INSL3 and GPRC6A expressions and the increase in serum testosterone and ucOC levels were observed. After evaluation of findings altogether, it is put forward that, for the first time in this study, although osteocalcin treatment made no significant difference in the number of Leydig cells, it increased the level of testosterone through improving the function of existing adult Leydig cells during normal postnatal development process and post-EDS regeneration. This positive correlation between osteocalcin-testosterone and osteocalcin-INSL3 is concluded to be independent of LH at in vivo conditions.
Highlights
Sex steroid hormones are extensively known to be necessary for skeletal development and bone health throughout adult life, except for reproductive functions [1,2,3], which could set new hypotheses related to the effects of the bone on the synthesis and secretion of steroid hormones. e most common noncollagenous protein in the bone is osteocalcin in 2 forms: Gla-OC and Glu-OC, according to carboxylated and uncarboxylated osteocalcin, respectively
Because of continued Leydig cell dysfunction, a decrease in INSL3 expression in the testicular tissue sections of subjects administered with GnRH antagonist together with osteocalcin (Figures 4(f ) and 5(f )) was similar to that of only-GnRH-antagonist-administered groups (Figures 4(g) and 5(g))
According to the results of immunohistochemical scoring, 3βHSD, INSL3, and GPRC6A immunoreactivity was significantly lower in testicular tissue sections of Group 1B, Group 1C, Group 2B, and Group 2C subjects administered with GnRH antagonist and GnRH antagonist together with osteocalcin when compared to control groups
Summary
Sex steroid hormones are extensively known to be necessary for skeletal development and bone health throughout adult life, except for reproductive functions [1,2,3], which could set new hypotheses related to the effects of the bone on the synthesis and secretion of steroid hormones. e most common noncollagenous protein in the bone is osteocalcin in 2 forms: Gla-OC and Glu-OC, according to carboxylated (cOC) and uncarboxylated (ucOC) osteocalcin, respectively. While the active form of Glu-OC (ucOC) is used as hormone, the Gla-OC (cOC) contained in the bone matrix is biologically inactive. E specific ucOC receptor in Leydig cells is GPRC6A which exists in the brain, heart, lung, spleen, kidney, skeletal muscle, adipose tissue, and pancreatic B cells, but not in the ovaries. UcOC has been reported to induce pancreatic B-cell proliferation and International Journal of Endocrinology insulin secretion, resulting in insulin sensitivity in the liver, muscle, and white fat [10,11,12,13,14,15]. The orally administered Gla-OC form is reported to be decarboxylated in stomach acidity and converted into Glu-OC, resulting in increased serum ucOC and insulin levels [16]
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