Abstract
In order to study the mechanisms of bone resorption induced by squamous cell carcinoma (SCC), the author analyzed bone resorbing substances released into the medium by an established SCC cell line Ca 9-22 PF. This cell line was derived from human gingival SCC and cultured in a protein-free medium. The analysis of bone resorption was carried out by the measurement of released 45Ca from pre-labeled mouse calvariae.The results were as follows:1) A dose dependent stimulation of bone resorbing activity was found by adding the cultured supernatant of Ca 9-22 PF cells.2) The bone resorption was due to the formation and activation of osteoclasts, because the stimulation was found only in live calvariae and was reduced by calcitonin treatment.3) About half of the 45Ca release stimulating effect was inhibited by indomethacin, an inhibitor of prostaglandin production.4) When the conditioned medium was fractionated by gel chromatography, the bone resorbing activity was found in multiple fractions. The molecular size in each fraction having a bone resorbing activity was 12000-16000, 16000-20000, 35000 and larger than 50000, respectively.5) The bone resorbing substance having the MW 12000-16000 was identified as IL-la by a specific radioimmunoassay and neutralization by antibody.6) The substance having the MW 16000-20000 was identified as PTHrP by stimulation of cAMP production in ROS 17/2 cells and by the Northern blot hybridization.7) The substance having the MW 35000 was identified as PDGF-AA by stimulation of proliferation in BALB 3 T 3 fibroblasts and neutralization by antibody.8) In addition to IL-1α, IL-1 β, PTHrP and PDGF-AA, the substances responsible for the stimulated bone resorption were identified as TGFα and TGFβ by the Northern blot analysis.9) The conditioned media of other SCC cell lines, HSC-2 PF, HSC-3 PF, HSC-4 PF, A 431 PF and ZAPF, also showed bone resorbing activity similar to Ca 9-22 PF. Bone resorbing factors were also identified to be about the same as those produced in Ca 9-22 PF by the Northern blot hybridization.In conclusion, it was speculated that the synergistic action of these substances produced by SCC are responsible for a marked increase in osteoclastic bone resorption and malignancy associated hypercalcemia.
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