C-TYPE NATRIURETIC PEPTIDE INCREASES BONE-RESORPTION IN 1,25-DIHYDROXYVITAMIN D-3 STIMULATED MOUSE BONE-MARROW CULTURES

Most agents that regulate osteoclast bone resorption exert their effec ts indirectly, through the osteoblast, Nitric oxide, which stimulates soluble guanylyl cyclase, has been reported to inhibit osteoclast bone resorption directly, by a cGMP-independent mechanism (1). In this rep ort, we demonstrate that C-type natriuretic peptide (CNP), an activato r of membrane-bound guanylyl cyclase, stimulates bone resorption by os teoclast-containing 1,25-dihydroxyvitamin D-3 (1,2 5-(OH)(2)D-3)-stimu lated mouse bone marrow cultures. Quantitative reverse transcription p olymerase chain reaction assays and anti-CNP immunocytochemistry were used to demonstrate that CNP is expressed in mouse marrow cells cultur ed in the presence, but not the absence, of 1,25-(OH)(2)D-3. mRNA for guanylyl cyclase type B, the receptor for CNP, was expressed in cultur es independent of 1,25-(OH)(2)D-3, CNP (1 and 10 mu M) elevated cGMP p roduction in marrow cultures to 350 and 870%, respectively, of control values, 10 mu M CNP increased osteoclast bone resorptive activity, me asured by the resorption area on whale dentine wafers, or by the NH4Cl -inhibitable release of [H-3]proline from radiolabeled bone chips, to 214 and 557% of control, respectively, without affecting osteoclast fo rmation, Bone resorption by the marrow cultures was inhibited by 7F9.1 , a monoclonal antibody raised against CNP, but not by control antibod ies. These results indicate that CNP is a potent activator of osteocla st activity and may be a novel local regulator of bone remodeling.