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Volume 271, Number 47, Issue of November 22, 1996 pp. 29839-29846
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Signal Transduction Pathways Mediating Parathyroid Hormone Stimulation of Bone Sialoprotein Gene Expression in Osteoblasts

(Received for publication, March 25, 1996, and in revised form, September 5, 1996)

From the Laboratory for the Study of Skeletal Disorders and Rehabilitation and Department of Orthopedic Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Bone sialoprotein is a major noncollagenous protein of bone. Parathyroid hormone (PTH) was shown to cause a 2-4-fold increase in the steady-state levels of bone sialoprotein mRNAs within primary cultures of embryonic osteoblasts. The induction could be mimicked by both forskolin and phorbol 12-myristate 13-acetate and was not inhibited by cycloheximide. Transient expression of a ~1200-base pair avian 5 bsp promoter/reporter construct demonstrated similar inductions as mRNA levels. Co-transfection of an expression plasmid encoding heat-stable inhibitor of cAMP-dependent protein kinase, a peptide inhibitor of PKA, decreased both the basal and PTH-induced bsp transcription, while co-expression of the catalytic subunit of PKA-induced bsp expression 3-fold. Protein kinase C activation, on the other hand, did not appear to work through its activation of c-fos, since co-transfection of an expression clone for c-fos had no effect. Interestingly, heat-stable inhibitor of cAMP-dependent protein kinase also inhibited the phorbol 12-myristate 13-acetate induction, suggesting that the protein kinase C acts through some form of interaction with the cAMP/PKA pathway. A half-cAMP response element site in the bsp promoter was identified as the cis-acting element that mediated the PTH response by the transient transfections with reporter constructs containing nested deletions of the promoter or a heterologous promoter containing the cAMP response element. In conclusion, these data indicate that PTH stimulation of bsp gene expression is specific to osteoblasts and mediated by changing cellular cAMP/PKA levels. They further suggest that although protein kinase C is capable of stimulating the gene by itself, it plays a minimal role in mediating the PTH induction of bone sialoprotein.

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