Divergent effects of protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide i (GF109203X) on bone resorption

Abstract

Activation of protein kinase C (PKC) has been suggested to play a role in bone resorption. However, phorbol esters, which activate PKC, have been reported to have both stimulatory and inhibitory effects on bone resorption. To study the role of PKC in bone resorption further, we have measured calcium release elicited by bone-resorbing hormones from isolated bones incubated with the PKC inhibitors staurosporine (ST) and the more PKC-selective ST analog bisindolylmaleimide I (GF109203X; GF). In fetal rat limb bone organ cultures, ST (1 μM) or GF (1 μM) significantly reduced the bone resorption induced by maximal concentrations of parathyroid hormone (PTH). However, when submaximal concentrations of PTH were used, lower concentrations of the two antagonists had divergent effects. GF (20–300 nM) acted solely as an antagonist, whereas ST (10–100 nM) significantly enhanced resorptive responses to PTH. ST also enhanced the bone resorption elicited by α-thrombin, tumor necrosis factor-α (TNF-α), and thyroxin (T4). ST alone had small stimulatory effects in some experiments. GF prevented the stimulatory effects of ST alone as well as the enhancing effect of ST on PTH-stimulated resorption. The divergent effects of ST and GF on the responses of bone to low concentrations of PTH and the ability of GF to antagonize the stimulatory effects of ST suggest that PKC isozymes have complex and even antagonistic effects on bone resorption.