PARATHYROID-HORMONE FRAGMENTS MAY STIMULATE BONE-GROWTH IN OVARIECTOMIZED RATS BY ACTIVATING ADENYLYL-CYCLASE

PTH is regarded conventionally as a catabolic hormone that stimulates osteoclastic resorption of bone. However, it has been known since 1932 that intermittent pulses of PTH stimulate bone formation in animals a nd humans. PTH independently activates two signal mechanisms: one that stimulates adenylyl cyclase and one that stimulates protein kinase C (PKC). The goal of this study was to use the 3- to 5-month-old ovariec tomized (OVX) rat model to determine which of the two signal mechanism s is responsible for the anabolic action of PTH on bone. OVX triggered a large loss of trabecular bone without significantly affecting the n ormal slow growth of cortical bone in the distal halves of the femora. Daily injections of human hPTH(1-34) fragment (1 nmol/100 g body weig ht), which stimulated both adenylyl cyclase and membrane-associated PK C activity in osteoblast-like ROS 17/2 rat osteosarcoma cells, stimula ted the growth of both cortical and trabecular bone in the OVX rats. D aily injections of the same dose of hPTH(1-31), which stimulated adeny lyl cyclase but not PKC in ROS 17/2 cells, stimulated trabecular bone growth in the OVX rats less effectively than hPTH(1-34), but it stimul ated cortical bone growth as rapidly and as dramatically as hPTH(1-34) . Injections of equimolar amounts of desamino-hPTH(1-34) [N-propionyl( 2-3)hPTH-amide], which stimulated PKC as strongly as hPTH(1-34) in ROS 17/2 cells but had a drastically reduced ability to stimulate adenyly l cyclase, or injections of recombinant hPTH(8-84) which stimulated PK C only in the ROS 17/2 cells, did not stimulate cortical or trabecular bone growth in the OVX animals. Thus, cyclic AMP and cyclic AMP-depen dent protein kinases may be the primary mediators of the anabolic acti on of intermittent pulses of PTH on bone in OVX rats.