Humoral Factors of Ascites Sarcoma 180 Stimulate Osteoblastic UMR 106-01 Cell Proliferation and Bone Resorption via Signal Transduction Pathways, Which Are Clearly Different from Those of Parathyroid Hormone

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概要

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• Ascites sarcoma 180 (S180A) is a transplantable tumor that induces hypercalcemia in tumorbearing 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 [<SUP>3</SUP>H]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 ([Ca<SUP>2+</SUP>]i), inositol 1, 4, 5-triphosphate (IP<SUB>3</SUB>), 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 [Ca<SUP>2+</SUP>]i and stimulated IP<SUB>3</SUB> 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 cyiosol 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 Sl80A-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 E<SUB>2</SUB> production by bone.

• 社団法人 日本薬理学会の論文

著者

• Suzuki Keiko

  Department of Pharmacology, School of Dentistry Showa University

• Yamada Shoji

  Department of Pharmacology, School of Dentistry Showa University

• Yamada Shoji

  <I>Department of Pharmacology, School of Dentistry Showa University</I>

関連論文

• Humoral Factors of Ascites Sarcoma 180 Stimulate Osteoblastic UMR 106-01 Cell Proliferation and Bone Resorption via Signal Transduction Pathways, Which Are Clearly Different from Those of Parathyroid Hormone

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