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© The Rockefeller University Press, 0021-9525/1998//409 $5.00
The Journal of Cell Biology, Volume 140, Number 2, , 1998 409-418

Bone Morphogenetic Protein Signaling Is Required for Maintenance of Differentiated Phenotype, Control of Proliferation, and Hypertrophy in Chondrocytes

Motomi Enomoto-Iwamoto^*, Masahiro Iwamoto, Yoshiki Mukudai^*, Yasuhiko Kawakami, Tsutomu Nohno, Yoshinobu Higuchi, Seiji Takemoto, Hideyo Ohuchi^||, Sumihare Noji^||, and Kojiro Kurisu

^* Department of Biochemistry, Department of Oral Anatomy and Developmental Biology, Osaka University Faculty of Dentistry, Osaka 565, Japan; Department of Molecular Biology, Kawasaki Medical School, Kurashiki 701-71, Japan; and ^|| Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Tokushima City 770, Japan

To examine the role of bone morphogenetic protein (BMP) signaling in chondrocytes during endochondral ossification, the dominant negative (DN) forms of BMP receptors were introduced into immature and mature chondrocytes isolated from lower and upper portions of chick embryo sternum, respectively. We found that control sternal chondrocyte populations 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 immature lower sternal (LS) chondrocytes led to a loss of differentiated functions; compared with control cells, the DN-BMPR- II–expressing LS chondrocytes 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 little alkaline phosphatase activity and type X collagen gene expression, while the control US cells produced both alkaline phosphatase and type X collagen. Both DN-BMPR-II–expressing US and LS chondrocytes failed 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 had little effect, while DN-BMPR-IB had similar but weaker effects compared with those of DN-BMPR-II. We conclude that BMP signaling, particularly that mediated by the type II BMP receptor, is required for maintenance of the differentiated phenotype, control of cell proliferation, and expression of hypertrophic phenotype.

Abbreviations used in this paper: APase, alkaline phosphatase; BMP, bone morphogenetic protein; BMPR, BMP receptor; DN, dominant negative; GAG, glycosaminoglycan; RT-PCR, reverse transcriptase PCR; US and LS, upper and lower sterna.

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