α-Catenin inhibits β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity and collagen type II expression in articular chondrocytes through formation of Gli3R.α-catenin.β-catenin ternary complex.
Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/β-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits β-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of β-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and β-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to β-catenin by α-catenin. The resulting inhibition of β-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on β-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate β-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·β-catenin, mediates Ihh-dependent activation of Wnt/β-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to β-catenin to inhibit β-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of β-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased β-catenin transcriptional activity during osteoarthritic cartilage destruction.
Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Jinseol
J
Rhee
Je-Hwang
JH
Ryu
Jin-Hong
JH
Kim
Churl-Hong
CH
Chun
Jang-Soo
JS
Chun
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000502:physiology; D024043:Collagen Type II / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000074290:Zinc Finger Protein Gli3; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D024043:Collagen Type II; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D000074290:Zinc Finger Protein Gli3; D051178:alpha Catenin; D051176:beta Catenin