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 expressed 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 assessed by [H-3]thymidine incorporation. Second, CNP stimulates cell hypertrophy as assessed by quantitative histology. Third, CNP stimulates cartilage matrix production as assessed by incorporation of (SO4)-S-35 into glycosaminoglycans. Natriuretic peptide receptor-B contains an intracellular guanylyl cyclase catalytic domain. We therefore hypothesized that cyclic GMP (cGMP) would reproduce the effects of CNP on fetal bones. Consistent with this hypothesis, we found that 8-Br-cGMP, like CNP, stimulates longitudinal growth and glycosaminoglycan synthesis. However, unlike CNP, cGMP inhibits proliferation of growth plate chondrocytes and has no effect on hypertrophy. We conclude that CNP stimulates longitudinal bone growth by increasing chondrocyte proliferation, chondrocyte hypertrophy, and cartilage matrix production. cGMP, a second messenger for CNP, reproduces some but not all of the effects of CNP, suggesting that other signal transduction mechanisms may also be involved.