The biological activities of parathyroid hormone (PTH) on bone are quite complex as demonstrated by its catabolic and anabolic activities on the skeleton. Although there have been many reports describing genes that are regulated by PTH in osteoblast cells, the goal of this study was to utilize a well-established in vivo PTH anabolic treatment regimen to identify genes that mediate bone anabolic effects of PTH. We identified a gene we named PTH anabolic induced gene in bone (PAIGB) that has been reported as brain and acute leukemia cytoplasmic (BAALC). Therefore, using the latter nomenclature, we have discovered that BAALC is a PTH-regulated gene whose mRNA expression was selectively induced in rat tibiae nearly 100-fold (maximal) by a PTH 1-34 anabolic treatment regimen in a time-dependent manner. Although BAALC is broadly expressed, PTH did not regulate BAALC expression in other PTH receptor expressing tissues and we find that the regulation of BAALC protein by PTH in vivo is confined to mature osteoblasts. Further in vitro studies using rat UMR-106 osteoblastic cells show that PTH 1-34 rapidly induces BAALC mRNA expression maximally by 4 h while the protein was induced by 8 h. In addition to being regulated by PTH 1-34, BAALC expression can also be induced by other bone forming factors including PGE(2) and 1,25 dihydroxy vitamin D(3). We determined that BAALC is regulated by PTH predominantly through the cAMP/PKA pathway. Finally, we demonstrate in MC3T3-E1 osteoblastic cells that BAALC overexpression regulates markers of osteoblast differentiation, including downregulating alkaline phosphatase and osteocalcin expression while inducing osteopontin expression. We also demonstrate that these transcriptional responses mediated by BAALC are similar to the responses elicited by PTH 1-34. These data, showing BAALC overexpression can mimic the effect of PTH on markers of osteoblast differentiation, along with the observations that BAALC is induced selectively with a bone anabolic treatment regimen of PTH (not a catabolic treatment regimen), suggest that BAALC may be an important mediator of the PTH anabolic action on bone cell function.

12-O-Tetradecanoylphorbol-13-acetate (TPA)-treated adult epidermis as well as untreated fetal and adult epidermis were investigated to elucidate the effect of TPA in terms of cell differentiation using techniques of ultrastructural stereology. Twenty-four hours after a single application of TPA, the treated epidermis was characterized by involutional changes, i.e., increased volume density of intercellular spaces and of mitochondria, vacuoles, and cytoplasmic ground substance in the basal layer. However, 48 h after application, the TPA-treated epidermis was very similar to fetal epidermis, i.e., high volume density of nuclei ribosomes, rough endoplasmic reticulum, membrane-coating granules, and keratohyalin granules, and low volume density of bundled filaments in the upper layers. These stereological data indicate that the changes observed 48 h after TPA treatment were related not only to increased cell proliferation but also to inhibition of cell differentiation expressed as a reversion of the adult differentiation patterns and the acquisition of fetal characteristics in all epidermal layers.