SIGNAL-TRANSDUCTION PATHWAYS MEDIATING PARATHYROID-HORMONE REGULATIONOF OSTEOBLASTIC GENE-EXPRESSION

Parathyroid hormone (PTH) plays a central role in regulation of calciu m metabolism. For example, excessive or inappropriate production of PT H or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormon es act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the e ffect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell inv olved in bone formation to one directing the process of bone resorptio n. In response to PTH, the osteoblast decreases collagen, alkaline pho sphatase, and osteopontin expression and increases production of osteo calcin, cytokines, and neutral proteases. Many of these changes have b een shown to be due to effects on mRNA abundance through either transc riptional or post-transcriptional mechanisms. However, the signal tran sduction pathway for the hormone to cause these changes is not complet ely elucidated in any case. Binding of PTH and PTHrP to their common r eceptor has been shown to result in activation of protein kinases A an d C and increases in intracellular calcium. The latter has not been im plicated in any changes in mRNA of osteoblastic genes. On the other ha nd activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanis ms linking PKA and PKC activation to changes in gene expression, parti cularly at the nuclear level. (C) 1994 Wiley-Liss, Inc.