Ultrastructural and cytochemical studies on cancer and apoptosis in bone.

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We examined the mechanisms of bone metastasis and bone invasion. The tumor mass was surrounded by a membrane consisting of fibroblastic cells. These cells were positive for ALP ase. TRAPase-positive cells were localized close to the ALP ase-positive cells and numerous osteoclasts were observed on the neighboring bone surfaces. It seems that PTHrP secreted by the tumor cells appears to stimulate differentiation of osteoclasts and bone resorption in a paracrine manner through PTH/PTHrP receptor-immunopositive osteoblastic cells. In bone metastatic, breast cancer cells produced VEGF and induced many CD31-positive blood vessels in bone. TRAPase-positive osteoclasts directly contacted to RANKL-positive cells. It seems that VEGF of the tumor cells induce growth of cancer and osteoclasts progenitor, and stimulate differentiation and activation of osteoclasts via RANKL of osteoblastic cells. Furthermore, we found that bisphosphonate inhibited the number of osteoclasts and blood vessels in bone metastatic area. We investigated the mechanism which a mutant ALPase induced bone disease in vitro. The mutant ALPase gene resulted in protein synthesis but not ER-to-Golgi apparatus trafficking. Then, osteoclasts apoptosis were studied in the tibia of rats treated with a bisphosphonate. They became devoid of ruffled borders and detached from bone surface, and showed formation of many vesicles and degradation of Golgi apparatus and DNA fragmentation. The majority of them are eliminated by macrophages, but there are some that escape into blood vessels. Furthermore, we found that bisphosphonates directly affect osteoclasts without mediating its deposition to the bone matrix.