Regulation of growth plate chondrogenesis by bone morphogenetic protein-2

Bone morphogenetic proteins (BMPs) regulate embryonic skeletal development. We hypothesized that BMP-2, which is expressed in the growth plate, also r egulates growth plate chondrogenesis and longitudinal bone growth. To test this hypothesis, fetal rat metatarsal hones were cultured for 3 days in the presence of recombinant human BMP-2. The addition of BMP-2 caused a concen tration-dependent acceleration of metatarsal longitudinal growth. As the ra te of longitudinal bone growth depends primarily on the rate of growth plat e chondrogenesis, we studied each of its three major components. BMP-2 stim ulated chondrocyte proliferation in the epiphyseal zone of the growth plate , as assessed by [H-3]thymidine incorporation. BMP-2 also caused an increas e in chondrocyte hypertrophy, as assessed by quantitative histology and enz yme histochemistry. A stimulatory effect on cartilage matrix synthesis, ass essed by (SO4)-S-35 incorporation into glycosaminoglycans, was produced onl y by the highest concentration of BMP-2. These BMP-2-mediated stimulatory e ffects were reversed by recombinant human Noggin, a glycoprotein that block s BMP-2 action. In the absence of exogenous BMP-2, Noggin inhibited metatar sal longitudinal growth, chondrocyte proliferation, and chondrocyte hypertr ophy, which suggests that endogenous BMPs stimulate longitudinal bone growt h and chondrogenesis. We conclude that BMP-2 accelerates longitudinal bone growth by stimulating growth plate chondrocyte proliferation and chondrocyt e hypertrophy.