Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia.
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.
Horiki
Mitsuru
M
Department of Orthopaedics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Imamura
Takeshi
T
Okamoto
Mina
M
Hayashi
Makoto
M
Murai
Junko
J
Myoui
Akira
A
Ochi
Takahiro
T
Miyazono
Kohei
K
Yoshikawa
Hideki
H
Tsumaki
Noriyuki
N
D000818:Animals; D000831:Animals, Newborn; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D048429:Cell Size / Q000187:drug effects / Q000235:genetics; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051785:Smad Proteins; D051898:Smad1 Protein; D051905:Smad6 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases