ROLE OF DUAL SIGNAL-TRANSDUCTION SYSTEMS IN THE STIMULATION OF BONE-RESORPTION BY PARATHYROID HORMONE-RELATED PEPTIDE - THE DIRECT INVOLVEMENT OF CAMP-DEPENDENT PROTEIN-KINASE

The present study was performed to compare the effect of parathyroid h ormone-related peptide (PTHrP) on bone resorption with that of parathy roid hormone (PTH) and clarify the participation of PTHrP-responsive d ual signal transduction systems involving cAMP-dependent protein kinas e (PKA) and calcium/protein kinase C (Ca/PKC) in the stimulation of bo ne resorption by PTHrP. Bone resorbing activity was estimated as the n umber of pits formed on the dentine slice and total area of pits per s lice in bone cells derived from 2 week-old mice. Human (h)PTHrP(1-34) (10(7)M) stimulated bone resorption as potent as hPTH-(1-34) (10(7)M) did. The stimulation of bone resorption by hPTHrP-(1-34) and hPTH-(1-3 4) was equally blocked by either simultaneous treatment with 10(-8)M e el calcitonin or pretreatment with 10-7 M [Nle8,18Tyr34]hPTH-(3-34)ami de. Rp-cAMPS, an antagonist in the activation of PKA, equally attenuat ed bone resorption stimulated by PTHrP as well as by PTH. A23187 (10(- 7) M) caused a significant stimulation of bone resorption. These findi ngs indicate the direct involvement of PKA activation and a contributo ry role of an increase in cytosolic calcium in the stimulation of bone resorption by PTHrP and suggest that PTHrP stimulates bone resorption presumably through the same mechanism as PTH does.