Connexin 43 and ERK regulate tension-induced signal transduction in human periodontal ligament fibroblasts

Periodontal ligament (PDL) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone. Connexin 43 (Cx43), a gap junction protein, is essential for bone homeostasis and regulates bone remodeling. However, the function of Cx43 in human PDL fibroblast-regulated bone remodeling has not yet been elucidated. In this study, human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5% elongation for different durations. We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal-regulated kinase (ERK) in human PDL fibroblasts after loading. We found that mechanical tension increased Cx43, which further upregulated osteogenic (e.g., RUNX2, Osterix, and OPG) and down-regulated osteoclastogenic (e.g., RANKL) signaling molecules. Suppressing Cx43 gene (Gja1) by siRNA inhibited the increase in osteogenesis-related molecules but enhanced RANKL expression. Similar to Cx43, activated ERK1/2 was also enhanced by mechanical tension and suppressed by Cx43 siRNA. Inhibition of ERK1/2 signaling using PD98059 reduced the tension-regulated increase in osteogenesis-related molecules but enhanced that of osteoclastogenesis-related ones. These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the Cx43-ERK1/2 signaling pathway. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1008-1014, 2015.