The receptor for advanced glycation end products (RAGE) is a cell surface multiligand receptor of the immunoglobulin superfamily, which participates in physiological and pathological processes such as neuronal development, diabetes, inflammation, neurodegenerative disorders, and cancer. A novel splice variant of RAGE-endogenous secretory decoy form (esRAGE) was recently identified and is thought to be a prospective candidate to modify these RAGE-associated conditions. Here, we investigated the expression and distribution of esRAGE and RAGE proteins with domain-specific antibodies. We studied a wide variety of adult normal human preparations obtained from surgical and autopsy specimens using a tissue microarray technique. The results revealed that esRAGE was widely distributed and we classified its expression into four patterns. In pattern A, the cytoplasm is stained diffusely in neurons, vascular endothelium, pneumocytes, mesothelium, pancreatic b cells, and macrophages/monocytes. In pattern B, dot-like granules are stained in the supranuclear regions facing the luminal surface of the bile ducts, salivary glands, digestive tracts, renal tubules, prostate, skin, thyroid, and bronchioles. Pattern C is represented by diffuse staining in the stromal area of the arterial walls. Pattern D shows diffuse and strong staining of secreted materials such as thyroidal colloid, crystals in renal tubular lumen, and glandular lumen in prostate. This study provides, for the first time, a histopathological basis for understanding the physiological roles of esRAGE in humans, and will contribute to elucidating the participation of esRAGE in pathological processes and to exploring novel diagnostic and therapeutic concepts.

Studies on the proliferation and differentiation of the cells in the rat anterior pituitary were reviewed. The mitotic rate of anterior pituitary is low in the control adult animal, but it increased by stimulation, such as by ablation of the target organ. A high mitotic rate was also reported during ontogenesis of the pituitary. Concomitant with this augmented mitosis, the number of those cells that are double-labeled with the marker of proliferation and the antibody to pituitary hormones increased as well. The percentage of these double-labeled cells in all the proliferating cells is less than 10%, suggesting that about 1/10 of the proliferating cells are involved in producing pituitary cells. This percentage for GH cells is 30-40% at most, suggesting very active production of them. The percentage of the double-labeled cell in all the hormone-producing cells is within 10% in all cell-types of the pituitary, including GH cells. When the proliferation is detected by a more sensitive method, this percentage increased to 20-40%, suggesting that the self-mitosis of the pituitary cells contributes considerably to their proliferation at a certain period during their ontogenesis.

To study the proliferation and differentiation of pituitary corticotrophs, we administered bromodeoxyuridine (BrdU) to pregnant rats at 15.5-21.5 days of gestation and to rat pups at 3, 7, and 28 days after birth. The pituitary sections of fetuses and pups were consecutively immunostained with anti-BrdU and anti-adrenocorticotropic hormone (ACTH) to detect proliferating cells and corticotrophs, respectively. The number of cells labeled with BrdU, ACTH, or both were counted. The diameters of their nuclei and the volume of the pituitary were measured. The BrdU-positive cells were around 76,000-96,000/mm3 during the period studied. The corticotrophs were first detected in the fetus at 15.5 days and they increased during the fetal and postnatal periods. The double-labeled cells were first detected in the 17.5-day fetus. They increased markedly at 19.5 days and comprised about one-quarter of the corticotrophs that increased in 24 h at this stage. These results indicate that: (1) at 15.5-18.5 days the corticotrophs were derived almost exclusively from undifferentiated cells; (2) during the later fetal and early postnatal periods, the proliferation of existing corticotrophs contributed, at least in part, to their increase; (3) about 1/20 of proliferating cells differentiated to corticotrophs when their increase was required.

Proliferation of somatotrophs and mammotrophs in the rat pituitary during late fetal and postnatal periods up to 4 weeks after birth was quantitatively studied with the double immunostaining of bromodeoxyuridine and the hormones produced by them. Somatotrophs were first detected in 18.5-day fetuses and rapidly increased in number throughout the periods studied. The cells labeled with both anti-BrdU and anti-GH were few in number until shortly before birth and then increased conspicuously during the first 10 days after birth. Mammotrophs were detected at gestational day 19.5 but they were few until the second week after birth, when their number began to increase rapidly. The percentage of the number of the cells double-labeled with both anti-BrdU and anti-GH to all somatotrophs was 8.3% at the most. This was about the same as that of corticotrophs during the late fetal period and that of thyrotrophs in the early postnatal period. In contrast, the percentage of double-labeled cells to all mammotrophs was 3.8% as a maximum, which is lower than the values for somatotrophs, corticotrophs, or thyrotrophs, indicating a smaller contribution of mitosis to mammotroph proliferation. It is possible that this smaller contribution is compensated for by transdifferentiation of cells committed to become the somatotroph lineage. However, coexistence of GH and PRL was not observed in the present material.

Pituitary glands from rat fetuses (gestational age 17.5-21.5 days) and rat pups (3, 7, 10, 14, 28 days old) were labeled with bromodeoxyuridine (BrdU) 2 h prior to sacrifice and embedded in paraffin. Sections were consecutively immunostained with anti-BrdU and anti-rat TSH. The number of cells stained with anti-BrdU, anti-rTSH, or both of them were counted. The area of the section and the volume of the pituitary were measured and the number of immunostained cells per mm3 or per pituitary was calculated. Thyrotrophs were few in 17.5 day-fetuses but increased thereafter, with a rapid increase during the 2nd week after birth. The number of cells labeled with both BrdU and TSH peaked at 7 days after birth. It was estimated that about 1/5 of the thyrotrophs increased during this period was derived from the mitosis of existing thyrotrophs.