12211438

pubmed:Citation

9

Parathyroid hormone (PTH) is a major regulator of osteoclast formation and activation, effects that are associated with reciprocal up- and down-regulation of RANKL and osteoprotegerin (OPG), respectively. The roles of specific downstream signals generated by the activated PTH/PTH-related protein (PTHrP) receptor (PTH1R), such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and phospholipase C/protein kinase C (PLC/PKC), in controlling RANKL and OPG expression and osteoclastogenesis remain uncertain. In MS1 conditionally transformed clonal murine marrow stromal cells, which support PTH-induced osteoclast formation from cocultured normal spleen cells, PTH(1-34) increased RANKL and macrophage colony-stimulating factor (M-CSF) mRNA expression and decreased that of OPG when present continuously for 7-20 days at 37 degrees C in the presence of dexamethasone (Dex). In cells precultured for 7 days and then treated with PTH(1-34), similar reciprocal regulation of RANKL and OPG occurred, maximally at 6-24 h, that was of greater amplitude than the changes induced by chronic (7-10 days) PTH exposure. These acute effects of PTH(1-34) were mimicked by PKA stimulators (8-bromoadenosine [8Br]-cAMP or forskolin [FSK]), blocked by the PKA inhibitor Rp-cAMPs but unaffected by the PKC inhibitor GF109203X. Amino-truncated PTH(1-34) analogs PTH(5-34) and PTH(7-34) neither increased cAMP production in MS1 cells nor regulated RANKL or OPG mRNA. Reciprocal RANKL/OPG mRNA regulation was induced in MS1 cells by PTH(3-34) but only at high concentrations that also increased cAMP. The highly PKA-selective PTH analog [Gly1,Arg19]human PTH(1-28) exerted effects similar to PTH(1-34) on RANKL and OPG mRNAs and on osteoclast formation, both in MS1/spleen cell cocultures and in normal murine bone marrow cultures. The direct PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (PMA) did not induce RANKL mRNA in MS1 cells, but it did up-regulate OPG mRNA and also antagonized osteoclast formation induced by PTH(1-34) in both MS1/spleen cocultures and normal bone marrow cultures. Thus, cAMP/PKA signaling via the PTH1R is the primary mechanism for controlling RANKL-dependent osteoclastogenesis, although direct PKC activation may negatively regulate this effect of PTH by inducing expression of OPG.

eng

IM

MEDLINE

0884-0431

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1667-79

pubmed-meshheading:12211438-Animals, pubmed-meshheading:12211438-Bone Marrow Cells, pubmed-meshheading:12211438-Calcium Signaling, pubmed-meshheading:12211438-Carrier Proteins, pubmed-meshheading:12211438-Cell Line, pubmed-meshheading:12211438-Cyclic AMP, pubmed-meshheading:12211438-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:12211438-Gene Expression, pubmed-meshheading:12211438-Glycoproteins, pubmed-meshheading:12211438-Male, pubmed-meshheading:12211438-Membrane Glycoproteins, pubmed-meshheading:12211438-Mice, pubmed-meshheading:12211438-Mice, Inbred C57BL, pubmed-meshheading:12211438-Osteoclasts, pubmed-meshheading:12211438-Osteoprotegerin, pubmed-meshheading:12211438-Parathyroid Hormone, pubmed-meshheading:12211438-Peptide Fragments, pubmed-meshheading:12211438-Protein Kinase C, pubmed-meshheading:12211438-RANK Ligand, pubmed-meshheading:12211438-RNA, Messenger, pubmed-meshheading:12211438-Receptor, Parathyroid Hormone, Type 1, pubmed-meshheading:12211438-Receptor Activator of Nuclear Factor-kappa B, pubmed-meshheading:12211438-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:12211438-Receptors, Parathyroid Hormone, pubmed-meshheading:12211438-Receptors, Tumor Necrosis Factor, pubmed-meshheading:12211438-Signal Transduction

Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells.

Journal Article, Research Support, U.S. Gov't, P.H.S.