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Published online 3 May 2004. doi:10.1083/jcb.200311015
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 3, 433-445
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Article

 Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia

Mitsuru Horiki1, Takeshi Imamura2, Mina Okamoto1, Makoto Hayashi2, Junko Murai1, Akira Myoui1, Takahiro Ochi1, Kohei Miyazono2,3, Hideki Yoshikawa1, and Noriyuki Tsumaki1

1 Department of Orthopaedics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
2 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan
3 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Noriyuki Tsumaki, Dept. of Orthopaedics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3552. Fax: 81-6-6879-3559. email: tsumaki-n{at}umin.ac.jp

Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs). However, their in vivo functions are largely unknown. Here, we generated transgenic mice overexpressing Smad6 in chondrocytes. Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes. Endochondral ossification during development in these mice was associated with almost normal chondrocyte proliferation, significantly delayed chondrocyte hypertrophy, and thin trabecular bone. The reduced population of hypertrophic chondrocytes after birth seemed to be related to impaired bone growth and formation. Organ culture of cartilage rudiments showed that chondrocyte hypertrophy induced by BMP2 was inhibited in cartilage prepared from Smad6 transgenic mice. We then generated transgenic mice overexpressing Smurf1 in chondrocytes. Abnormalities were undetectable in Smurf1 transgenic mice. Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice. These results provided evidence that Smurf1 supports Smad6 function in vivo.

Key Words: chondrocyte; hypertrophy; osteopenia; dwarfism; transgenic mice

Abbreviations used in this paper: BMP, bone morphogenetic protein; BMPR, BMP receptor; Col10a1, type X collagen gene; Col11a2, {alpha}2(XI) collagen chain gene; Col2a1, type II collagen gene; d.p.c., days post coitus; G0, generation zero; rhBMP2, recombinant human BMP2; R-Smads, receptor-regulated Smads; Smurf1, Smad ubiquitin regulatory factor 1; TRAP, tartate-resistant acid phosphatase.


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