Kazunori Hamamura, Andy Chen, Nancy Tanjung, Hui B Sun and Hiroki Yokota
Osteoarthritis is a major cause of disability in the adult population. Exercise is commonly prescribed, but the mechanisms underlying mechanotransduction of joint tissues are not well understood. Since Lrp5 is an important mechano-sensitive receptor in Wnt signaling, we examined its role in the mRNA expression of A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5), a major proteolytic aggrecanase that degrades extracellular matrix in articular cartilage. Using genome-wide expression data for C28/I2 chondrocytes with and without Lrp5-specific siRNA, we employed a systems biology approach and built a regulatory network model. Experimental data revealed that silencing Lrp5 significantly altered Wnt signaling gene expression and elevated the mRNA level of ADAMTS5 and several cytokines. A series of experiments using RNA interference showed that the expression of ADAMTS5 was at least in part stimulated by p38 MAPK and IL1β, while Lrp5 acted as a suppressor of their upregulation. Regulatory network analysis using an algorithm predicted the potential involvement of Wnt3a, Myc and CCAAT/Enhancer-Binding Protein β (CEBPB). Collectively, the systems biology approach helped develop an Lrp5-mediated network model in regulation of ADAMTS5, and the model predicted that a secretary factor such as Wnt3a might be involved in Lrp5-mediated homeostasis of ADAMTS5.
