Effects of Hypercalcemia-Producing Tumor Extract and Parathyroid Hormone on Osteoclast Ultrastructure

Abstract

Hypercalcemia is a frequent complication of cancer. Recently, parathyroid hormone-related protein has been isolated from tumors associated with this syndrome. In the present study, the effects of tumor-derived hypercalcemic factor and bovine parathyroid hormone (PTH) on bone were compared in an organ culture system using calvarial bones from newborn mice. Mouse calvaria were incubated for 72 h with control medium or media containing 0.15 mg/ml tumor extract (TE) or 2 × 10^–9M PTH. Bone resorption as assessed by the amount of calcium released into the medium and the number of osteoclasts counted on light microscopy, was increased by both PTH and TE. On electron microscopy areas for cytoplasm ruffled border and clear zone were statistically increased in PTH- and TE-treated calvaria as compared to control. These values were not significantly different between PTH- and TE-treated calvaria. The study therefore demonstrates that the ultrastructural changes in osteoclasts induced by the hypercalcemia-producing TE are similar to those induced by PTH.

The effects of high dose of parathyroid hormone on fetal osteoclasts and their precursors in vivo: An ultrastructural‐cytochemical study

“…In our experimental study, high dose PTH caused the appearance of more abundant preosteoclasts, including very young preosteoclasts and a n unusual type of binucleated preosteoclast as well as apparently mononu- clear osteoclasts, compared with those in the controls. These preosteoclasts and osteoclasts exhibited not only changes in the cytoplasmic organelles, but also far more remarkable morphologic changes than those in our controls or in any other prior report (Lucht and Maunbach, 1973;Holtrop et al, 1974;King et al, 1978;Klaushofer et al, 1989;Barengolts et al, 1990).…”

“…Several studies on the ultrastructural changes in osteoclasts after administration of parathyroid hormone (PTH) have revealed that PTH causes an increase in the number of osteoclasts and that it activates osteoclasts to resulting in an increase in various cytoplasmic organelles, as well as in the extent of the clear zone and ruffled border regions (Lucht and Maunbach, 1973; 0 1995 WILEY-LISS. INC Holtrop et al, 1974;King et al, 1978;Miller et al, 1984;Klaushofer et al, 1989;Barengolts et al, 1990).…”

Substrate Recognition by Osteoclast Precursors Induces C-src/Microtubule Association

“…Identification and localization of these bone-degrading proteins brought realization that polarization is a major event in development of the anatomical and functional osteoclast phenotype. Specifically, entities such as the vacuolar proton pump (H ϩ -ATPase) (7), mannose-6-phosphate receptor (4,6,27), and lysosomal enzymes (22), all of which appear to mediate skeletal degradation, target to the bone-apposed plasma membrane. The molecules governing osteoclast polarization remained enigmatic until generation of the c-srcϪ/Ϫ mouse, whose osteoclasts lack Similar results were reproduced when using anti-c-src polyclonal and antitubulin monoclonal antibodies, followed by the relevant secondary-labeled antibodies (data not shown).…”