The Effect of Parathyroid Extract on Cellular Activity and Plasma Calcium Levels in Vivo

Abstract

SUMMARY Parathyroid hormone has a direct effect on the osteoclast population present at the time of administration of the hormone. There was a significant stimulation of nuclear RNA synthesis at the earliest time (1½ hr.) at which the measurement could be made. This is followed by increased production of cytoplasmic RNA which reaches its maximum after a considerable time-lag (7 to 12 hr. after parathyroid extract (PTE)). The increase in cytoplasmic RNA is accompanied by a corresponding stimulation of protein and mucoprotein synthesis in the osteoclasts and the effect persists at least until 24 hr. This time-lag and the relatively long duration of the effect on protein synthesis can be correlated approximately with the effect on the plasma calcium level. It is suggested therefore that the rise in plasma calcium is mainly due to the increased cellular activity of the osteoclasts and the resulting increased bone resorption. The opposite effect on the osteoblast system has about the same time-sequence and would complement the effect on the osteoclast system. At about the same time as the maximum increase in cellular activity in the osteoclasts is observed, a significant effect on RNA synthesis in the endosteal mesenchymal cells, the precursors of the osteoclasts, becomes apparent. This is closely followed by a rise in the number of osteoclasts which is first apparent at 17 hr. after PTE and is maximal by 24 hr. Consequently, the rise in the number of osteoclasts is a secondary effect and is not responsible for the initial rise in plasma calcium which occurred much earlier. It is suggested that the increase in osteoclast numbers follows as a result of the increased metabolic activity of the osteoclast population present when the hormone was injected. There is a depression of RNA synthesis in both the osteoblasts and their precursors, the preosteoblasts. This means that the hormone has opposite effects, not only on the osteoblasts and osteoclasts, but also on their respective precursors, indicating that osteoprogenitor cells contain a mixture of cells with two main lines, those differentiating in an osteoblastic or osteoclastic direction, respectively.

The preosteoclast and its cytodifferentiation into the osteoclast: Ultrastructural and histochemical studies of rat fetal parietal bone.

“…It is thought that in such a resting area, preosteoclasts come into contact with the exposed mineralized bone surface, possibly becoming a new modeling site where they differentiate, induce other preosteoclasts, and further aggregate and fuse to form osteoclasts. This tentative conclusion not only coincides with the hypothesis by RODAN and MARTIN (1981) that a change in shape of the osteoblasts controls bone resorption by the osteoclast, but also explains the fact that PTH induces increased numbers of the osteoclasts (BINGHAM et al, 1969;HOLTROP et al, 1974 The locations of the peroxidase activity in the metaphysis of a 4 day old rat. An intense reaction product is seen only in the specific granules of the mvelocyte (11) hot not in the osteoclast (OC).…”

“…Moreover, electron microscopic autoradiography using 3H-thymidine by SCOTT (1967) distinguished two types of osteogenic cells: a spindle cell type (A-cell) which she called a preosteoblast and a round cell type (B-cell) which she called a preosteoclast. This view was supported by BINGHAM et al (1969), who investigated the effect of parathyroid hormone on the RNA synthesis of bone cells. The presence of these two types of cells was further confirmed by various electron microscopic investigations (CAMERON, 1972;GOTHLIN, 1973;LUK et al, 1974a, b;KURIHARA, 1977;RIFKIN et al, 1980).…”

Induction of osteoclast formation by parathyroid hormone depends on an action on stromal cells

“…Following an injection of PTH, there is a rapid increase in the activity of pre-existing osteoclasts, followed by an increase in osteoclast numbers (Bingham et al 1969, Baron & Vignery 1981. It is believed that PTH increases the resorptive activity of pre-existing osteoclasts through a primary hormonal interaction with cells of the osteoblastic lineage, which possess PTH receptors and responsiveness (Chambers 1980, Rodan & Martin 1981, while osteoclasts have been found in most (Rouleau et al 1986(Rouleau et al , 1988(Rouleau et al , 1990 but not all (Rao et al 1983, Teti et al 1991, Agarwala & Gay 1992 studies to lack PTH receptors, and do not show a direct functional response to the hormone (Chambers et al 1985).…”

DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones.

“…While there is good evidence that the osteoclast precursor cell is derived from a hematopoietic stem cell (5-7), little is known about the effect of resorptive stimuli on the replication of this precursor or the relationship of cell replication to bone resorption. Parathyroid hormone (PTH)' is an important stimulator of bone resorption both in vivo and in vitro, and increases the number of osteoclasts in bone (8)(9)(10). PTH also increases DNA synthesis in bone cells (2,11,12,13).…”