Regulation of fetal rat bone growth by C-type natriuretic peptide and cGMP

C-type natriuretic peptide (CNP) and its high affinity receptor-B are expre ssed in fetal bones. Here we show that CNP accelerates longitudinal growth of fetal rat metatarsal bones in organ culture by several mechanisms. First , CNP stimulates chondrocyte proliferation in the proliferative zone as ass essed by [H-3]thymidine incorporation. Second, CNP stimulates cell hypertro phy as assessed by quantitative histology. Third, CNP stimulates cartilage matrix production as assessed by incorporation of (SO4)-S-35 into glycosami noglycans. Natriuretic peptide receptor-B contains an intracellular guanyly l cyclase catalytic domain. We therefore hypothesized that cyclic GMP (cGMP ) would reproduce the effects of CNP on fetal bones. Consistent with this h ypothesis, we found that 8-Br-cGMP, like CNP, stimulates longitudinal growt h and glycosaminoglycan synthesis. However, unlike CNP, cGMP inhibits proli feration of growth plate chondrocytes and has no effect on hypertrophy. We conclude that CNP stimulates longitudinal bone growth by increasing chondro cyte proliferation, chondrocyte hypertrophy, and cartilage matrix productio n. cGMP, a second messenger for CNP, reproduces some but not all of the eff ects of CNP, suggesting that other signal transduction mechanisms may also be involved.