Regulation of Tenomodulin Expression Via Wnt/β-catenin Signaling in Equine Bone Marrow-derived Mesenchymal Stem Cells.
Tenomodulin has been recognized as a biomarker for tendon differentiation, and its gene expression is regulated by several transcription factors including Scleraxis and Mohawk. In this study, we found a novel regulatory mechanism of tenomodulin expression. Equine bone marrow-derived mesenchymal stem cells (BMSCs) in monolayer culture showed a low mRNA level of tenomodulin in comparison with the level in the tendon. When cultured in collagen gel containing a glycogen synthase kinase-3 (GSK-3) inhibitor (BIO), expression of tenomodulin in BMSCs increased up to the level in the tendon. Participation of GSK-3 in its gene expression was further demonstrated by a gene silencing experiment with small interference RNA corresponding to GSK-3, suggesting that Wnt/β-catenin signaling mediated expression of tenomodulin. These results were confirmed by nuclear translocation of β-catenin in BIO-treated BMSCs cultured in collagen gel. Under this culture condition, expression of tenomodulin-related transcription factors including Scleraxis and Mohawk was not affected, suggesting that Wnt/β-catenin signaling was independent from these transcription factors. Additionally, BIO strongly enhanced expression of type XIV collagen in collagen-embedded BMSCs up to the level in the tendon, and other tendon-related extracellular matrix components such as decorin and fibromodulin were also upregulated. Taken together, these results indicated that activation of Wnt/β-catenin signaling could induce differentiation of BMSCs into tenomodulin-expressing tendon cells in collagen gel.
Department of Tissue Physiology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan.
Shihori
S
Miyabara
Department of Tissue Physiology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan.
Yohei
Y
Yuda
Laboratory of Clinical Science and Pathobiology, Equine Research Institute, Japan Racing Association, Tochigi 320-8056, Japan.
Yoshinori
Y
Kasashima
Laboratory of Clinical Science and Pathobiology, Equine Research Institute, Japan Racing Association, Tochigi 320-8056, Japan.
Atsutoshi
A
Kuwano
Department of Tissue Physiology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan.
Katsuhiko
K
Arai
BMSCs; ECM; Wnt signaling; tendon; tenomodulin