Stimulation of femoral trabecular bone growth in ovariectomized rats by human parathyroid hormone (hPTH)-(1-30)NH2

It has been proposed that intermittent bursts of adenylyl cyclase and the s urges of cyclic AMP (cAMP) they produce can trigger PTH's bone anabolic act ion without the activation of phospholipase-C (PLC). This was based on the osteogenic action in ovariectomized (OVX) rats of hPTH-(1-31)NH2, which can stimulate adenylyl cyclase but not PLC in ROS 17/2 rat osteosarcoma cells, and the osteogenic impotence of fragments such as 1-desamino-hPTH-(1-34) a nd hPTH-(8-84) which strongly stimulate PLC but not adenylyl cyclase. But t his seems to have been disproven by the inability of hPTH-(1-30)NH2 to stim ulate bone growth despite its having hPTH-(1-31)NH2's ability to strongly s timulate adenylyl cyclase but not PLC in cells with rat type1 PTH/PTHrP rec eptors. Because of the importance of hPTH-(1-30)NH2's apparent osteogenic i mpotence for knowing how PTH triggers bone growth, we have reinvestigated t he fragment's ability to stimulate trabecular bone growth in the femurs of young OVX rats and have found it to be strongly osteogenic at doses 2-10 ti mes higher than the highest dose used previously. Thus, 6 weeks of once-dai ly subcutaneous injections of 10-50 nmol of hPTH-(1-30)NH2/100 g of body we ight into young rats starting 2 weeks after OVX significantly increased the femoral trabecular volume and mean thickness of individual trabeculae abov e those in sham-operated control rats. In OVX rats treated with 50 nmol of hPTH-(1-30)NH2/100 g of body weight, the trabecular volume was 2.6 times hi gher and the mean trabecular thickness nearly 4 times higher than in the sh am-operated control rats. This very large increase in the mean trabecular t hickness was as much as the increase induced by 2 nmol/100 g of body weight of hPTH-(1-31)NH2, [Leu(27)]cyclo(Glu(22)-Lys(26))-hPTH-( 1-31)NH2, hPTH-( 1-34)NH2 and [Leu(27)]cyclo(Glu(22)-Lys(26))-hPTH-(1-34)NH2 These results h ave removed a major objection to the proposal that PTH's osteogenic action in rats can be triggered solely by intermittent surges of cAMP and the burs ts of cAMP-dependent protein kinase activity they cause.