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First published online December 31, 2003
doi: 10.1242/10.1242/jcs.00866
Research Article |
1 Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
2 Teijin Institute for Biomedical Research, Teijin Ltd., Hino, Tokyo 191-8512, Japan
3 Department of Orthodontics and Dentofacial Orthopedics, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan
4 Department of Orthopaedic Surgery, Thomas Jefferson Medical College, Philadelphia PA 19107, USA
Author for correspondence (e-mail: komorit{at}imed3.med.osaka-u.ac.jp)
Accepted 9 September 2003
Runx2 (runt-related transcription factor 2) is an important transcription factor for chondrocyte differentiation as well as for osteoblast differentiation. To investigate the function of Runx2 in chondrocytes, we isolated chondrocytes from the rib cartilage of Runx2-deficient (Runx2–/–) mice and examined the effect of Runx2 deficiency on chondrocyte function and behavior in culture for up to 12 days. At the beginning of the culture, Runx2–/– chondrocytes actively proliferated, had a polygonal shape and expressed type II collagen; these are all characteristics of chondrocytes. However, they gradually accumulated lipid droplets that stained with oil red O and resembled adipocytes. Northern blot analysis revealed that the expression of adipocyte-related differentiation marker genes including PPAR
(peroxisome proliferator-activated receptor ), aP2 and Glut4 increased over time in culture, whereas expression of type II collagen decreased. Furthermore, the expression of Pref-1, an important inhibitory gene of adipogenesis, was remarkably decreased. Adenoviral introduction of Runx2 or treatment with transforming growth factor-ß, retinoic acid, interleukin-1ß, basic fibroblast growth factor, platelet-derived growth factor or parathyroid hormone inhibited the adipogenic changes in Runx2–/– chondrocytes. Runx2 and transforming growth factor-ß synergistically upregulated interleukin-11 expression, and the addition of interleukin-11 to the culture medium reduced adipogenesis in Runx2–/– chondrocytes. These findings indicate that depletion of Runx2 resulted in the loss of the differentiated phenotype in chondrocytes and induced adipogenic differentiation in vitro, and show that Runx2 plays important roles in maintaining the chondrocyte phenotype and in inhibiting adipogenesis. Our findings suggest that these Runx2-dependent functions are mediated, at least in part, by interleukin-11.
Key words: Runx2, Cbfa1, Chondrocyte, Adipocyte, TGF-ß, IL-11
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