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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
Author(s) -
Kondo Hisatomo,
Guo Jun,
Bringhurst F. Richard
Publication year - 2002
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2002.17.9.1667
Subject(s) - medicine , endocrinology , rankl , parathyroid hormone , forskolin , osteoprotegerin , cyclic adenosine monophosphate , protein kinase a , osteoclast , chemistry , protein kinase c , stromal cell , bone resorption , adenosine monophosphate , receptor , adenosine , signal transduction , biology , kinase , activator (genetics) , calcium , biochemistry
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°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 [Gly 1 ,Arg 19 ]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.