Compression induces Ephrin-A2 in PDL fibroblasts via c-fos

Ephrin-a2-epha2 and ephrin-b2-ephb4 interactions have been implicated in the regulation of bone remodeling. we previously demonstrated a potential role for members of the eph-ephrin family of receptor tyrosine kinases for bone remodeling during orthodontic tooth movement: compression-dependent upregulation of ephrin-a2 in fibroblasts of the periodontal ligament (pdl) attenuated osteogenesis in osteoblasts of the alveolar bone. however,factors affecting the regulation of ephrin-a2 expression upon the application of compressive forces remained unclear. here,we report a mechano-dependent pathway of ephrin-a2 induction in pdl fibroblasts (pdlfs) involving extracellular signal-regulated kinases (erk) 1/2 and c-fos. pdlf subjected to compressive forces (30.3 g/cm2) upregulated c-fos and ephrin-a2 mrna and protein expression and displayed increased erk1/2 phosphorylation. inhibition of the map kinase kinase (mek)/erk1/2 pathway using the specific mek inhibitor u0126 significantly reduced ephrin-a2 messenger rna upregulation upon compression. silencing of c-fos using a small interfering rna approach led to a significant inhibition of ephrin-a2 induction upon the application of compressive forces. interestingly,ephrin-a2 stimulation of pdlf induced c-fos expression and led also to the induction of ephrin-a2 expression. using a reporter gene construct in murine 3t3 cells,we found that ephrin-a2 was able to stimulate serum response element (sre)-dependent luciferase activity. as the regulation of c-fos is sre dependent,ephrin-a2 might induce c-fos via sre activation. taken together,we provide evidence for an erk1/2- and c-fos-dependent regulation of ephrin-a2 in compressed pdlf and suggest a novel pathway for ephrin-a2 induction emanating from ephrin-a2 itself. we showed previously that ephrin-a2 at compression sites might contribute to tooth movement by inhibiting osteogenic differentiation. the regulatory pathway of ephrin-a2 induction during tooth movement identified in this study might be accessible for pharmacological interventions. © international & american associations for dental research 2015.