BONE MORPHOGENETIC PROTEIN SIGNALING IS REQUIRED FOR MAINTENANCE OF DIFFERENTIATED PHENOTYPE, CONTROL OF PROLIFERATION, AND HYPERTROPHY IN CHONDROCYTES

To examine the role of bone morphogenetic protein (BMP) signaling in c hondrocytes during endochondral ossification, the dominant negative (D N) forms of BMP receptors were introduced into immature and mature cho ndrocytes isolated from lower and upper portions of chick embryo stern um, respectively. We found that control sternal chondrocyte population s expressed type IA, IB, and II BMP receptors as well as BMP-4 and -7, Expression of a DN-type II BMP receptor (termed DN-BMPR-II) in immatu re lower sternal (LS) chondrocytes led to a loss of differentiated fun ctions; compared with control cells, the DN-BMPR-II-expressing LS chon drocytes proliferated more rapidly, acquired a fibroblastic morphology , showed little expression of type II collagen and aggrecan genes, and upregulated type I collagen gene expression. Expression of DN-BMPR-II in mature hypertrophic upper sternal (US) chondrocytes caused similar effects. In addition, the DN-BMPR-II-expressing US cells exhibited li ttle alkaline phosphatase activity and type X collagen gene expression , while the control US cells produced both alkaline phosphatase and ty pe X collagen. Both DN-BMPR-II-expressing US and LS chondrocytes faile d to respond to treatment with BMP-2. When we examined the effects of DN forms of types IA and IB BMP receptors, we found that DN-BMPR-IA ha d little effect, while DN-BMPR-IB had similar but weaker effects compa red with those of DN-BMPR-II. We conclude that BMP signaling, particul arly that mediated by the type II BMP receptor, is required for mainte nance of the differentiated phenotype, control of cell proliferation, and expression of hypertrophic phenotype.