Increased expression of G11α in osteoblastic cells enhances parathyroid hormone activation of phospholipase C and AP‐1 regulation of matrix metalloproteinase‐13 mRNA

Feb 5, 2005Journal of cellular physiology

Higher levels of G11alpha in bone-forming cells increase parathyroid hormone activation of enzymes and gene regulation involved in bone remodeling

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Abstract

Transfection with G(11)alpha cDNA resulted in a 5-fold increase in PTH-stimulated phospholipase C activity.

PTH stimulation of adenylyl cyclase activity did not change with increased G(11)alpha levels.
Increased G(11)alpha protein enhanced the translocation of specific protein kinase C (PKC) isoforms to the cell membrane and nucleus.
MMP-13 mRNA levels increased with all doses of PTH in G(11)alpha-transfected cells.
Maximal PTH-stimulation of c-jun mRNA showed a 2.5 +/- 0.35 fold increase, with smaller but significant increases in c-fos.
The increase in c-jun, c-fos, and MMP-13 expression was blocked by a selective PKC inhibitor.

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In osteoblasts parathyroid hormone (PTH) stimulates the PTH/PTH-related peptide (PTHrP) receptor (PTH1R) that couples via G(s) to adenylyl cyclase stimulation and via G(11) to phospholipase C (PLC) stimulation. We have investigated the effect of increasing G(11)alpha levels in UMR 106-01 osteoblastic cells by transient transfection with cDNA encoding G(11)alpha on PTH stimulation of PLC and protein kinase C (PKC) as well as PTH regulation of mRNA encoding matrix metalloproteinase-13 (MMP-13). Transfection with G(11)alpha cDNA resulted in a 5-fold increase in PTH-stimulated PLC activity with no change in PTH-stimulated adenylyl cyclase. PTH-induced translocation of PKC-betaI, -delta, and -zeta to the cell membrane and PKC-zeta to the nucleus was also increased. Increased G(11)alpha protein resulted in increased stimulation of MMP-13 mRNA levels at all doses of PTH. There was a 2.5 +/- 0.35 fold increase in maximal PTH-stimulation of c-jun mRNA and smaller but significant increases in c-fos accompanied by increased basal and PTH-stimulated AP-1 binding in cells expressing increased G(11)alpha. Runx-2 mRNA and protein levels were not significantly increased by increased G(11)alpha expression. The increase in PTH stimulation of c-jun, c-fos, and MMP-13 in G(11)alpha-transfected cells were all blocked by bisindolylmaleimide I, a selective inhibitor of PKC. These results demonstrate that regulation of the PLC pathway through the PTH1R is significantly increased by elevating expression of G(11)alpha in osteoblastic cells. This leads to increased PTH stimulation of MMP-13 expression by increased stimulation of AP-1 factors c-jun and c-fos.

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Increased expression of G11α in osteoblastic cells enhances parathyroid hormone activation of phospholipase C and AP‐1 regulation of matrix metalloproteinase‐13 mRNA

Abstract

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