No abstract

Although there is evidence that protein tyrosine kinase inhibitors (PTKIs) suppress bone resorption activity, the mechanism of action of these compounds on osteoclastic bone resorption remains obscure. In the present study, we investigated the effect of PTKIs on cytosolic Ca(2+) concentration ([Ca(2+)](i)) and on the cytoskeleton in rat osteoclasts. The PTKIs, genistein and herbimycin A, reversibly elevated [Ca(2+)](i) measured by fura-2 microfluorimetry. The PTKI-induced increase was abolished by omission of extracellular Ca(2+), but was not attenuated by depletion of Ca(2+) stores. The PTKI-induced increase was inhibited by addition of La(3+) and Ni(2+), but not abolished by dihydropyridine (DHP) Ca(2+) channel blockers. Genistin, an inactive analogue of genistein, had no effect on [Ca(2+)](i). In the cytoskeleton assay, genistein rapidly disrupted the actin ring formation that serves as a marker for the resorbing state of osteoclasts. Disruption of the actin ring formation was also diminished in Ca(2+)-free extracellular solution. These results suggest that PTKIs in rat osteoclasts elevate [Ca(2+)](i) via activation of a DHP-insensitive, nonspecific Ca(2+) entry pathway and disrupt the formation of actin rings, resulting in suppression of bone resorption activity. The regulation of this Ca(2+)-influx by PTKIs is likely to contribute to inhibition of bone resorption by these compounds.

Excessive mechanical stress (MS) during hyperocclusion is known to result in disappearance of the alveolar hard line, enlargement of the periodontal ligament (PDL) space, and destruction of alveolar bone, leading to occlusal traumatism. We hypothesized that MS induces expression of osteoclastogenesis-associated chemokines in PDL tissue, resulting in chemotaxis and osteoclastogenesis during occlusal traumatism. We examined the effect of MS on relationships between chemokine expression and osteoclastogenesis using in vivo and in vitro hyperocclusion models. In an in vitro model, intermittent stretching-induced MS was shown to up-regulate the expression of CC chemokine ligand (CCL)2, CCL3, and CCL5 in PDL cells. The expression levels of CCL2 in PDL tissues, its receptor CCR2 in pre-osteoclasts, and tartrate-resistant acid-phosphatase-positive cells in alveolar bone were significantly up-regulated 4-7 days after excessive MS during hyperocclusion in in vivo rodent models. Hyperocclusion predominantly induced CCL2 expression in PDL tissues and promoted chemotaxis and osteoclastogenesis, leading to MS-dependent alveolar bone destruction during occlusal traumatism.

No abstract

Intracavitary FdUrd chemotherapy may be useful for the treatment of small-volume tumors.