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Humoral Factors of Ascites Sarcoma 180 Si mulate Osteoblastic UMR 106-01 Cell Proliferation and Bone Resorption via Signal Transduction Pathways, Which Are Clearly Different from Those of Parathyroid Hormone
Author(s) -
Keiko Suzuki,
Shoji Yamada
Publication year - 1996
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.72.149
Subject(s) - endocrinology , medicine , parathyroid hormone , protein kinase c , bone resorption , chemistry , signal transduction , diacylglycerol kinase , resorption , biology , calcium , biochemistry
Ascites sarcoma 180 (S180A) is a transplantable tumor that induces hypercalcemia in tumor-bearing mice and stimulates bone resorption in cultured neonatal mouse calvaria without parathyroid hormone (PTH)-like activity. The serum-free conditioned media of S180A cell cultures (S180A-CM) stimulated [3H]thymidine incorporation (178.3% of the control) and inhibited alkaline phosphatase activity (39.0% of the control) in the osteoblastic osteosarcoma cell line UMR 106-01, contrary to PTH. To investigate signal transduction by S180A-CM, we determined the levels of intracellular free calcium ([Ca2+]i), inositol 1,4,5-triphosphate (IP3), 1,2-diacylglycerol (DAG), phosphatidylcholine (PC) and protein kinase (PK) C activity in UMR 106-01 cells. PTH and PTH-related protein (PTHrP), both potent bone-resorbing factors (BRFs), caused an increase in [Ca2+]i and stimulated IP3 production, whereas S180A-CM had little or no effect on these parameters. On the other hand, S180A-CM stimulated DAG production, accompanied by PC breakdown, and the translocation of PKC activity from the cytosol to the membrane fraction. Sphingosine, a specific PKC inhibitor, inhibited bone-resorbing activity (BRA) in S180A-CM more effectively than PTH or PTHrP-stimulated resorption. H-7, an inhibitor of both cAMP-dependent PKA and PKC, completely inhibited BRA in S180A-CM. These results suggest that BRFs of S180A-CM stimulate osteoblastic cell proliferation and bone resorption via two signal transduction pathways, which are different from those of PTH: 1) activation of PKC by DAG resulting from PC hydrolysis and 2) activation of PKA subsequent to prostaglandin E2 production by bone.

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