RETRACTED: Proepithelin Stimulates Growth Plate Chondrogenesis via Nuclear Factor-κB-p65-dependent Mechanisms (Retracted article. See vol. 295, pg. 8874, 2020)

Proepithelin, a previously unrecognized growth factor in cartilage, has recently emerged as an important regulator for cartilage formation and function. In the present study, we provide several lines of evidences in proepithelin-mediated induction of cell proliferation, differentiation, and apoptosis in the metatarsal growth plate. Proepithelin-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by pyrrolidine dithiocarbamate, a known NF-kappa B inhibitor. In rat growth plate chondrocytes, proepithelin induced NF-kappa B-p65 nuclear translocation, and nuclear NF-kappa B-p65 initiated its target gene cyclin D1 to regulate chondrocyte functions. The inhibition of NF-kappa B-p65 expression and activity (by p65 short interfering RNA (siRNA) and pyrrolidine dithiocarbamate, respectively) in chondrocytes reversed the proepithelin-mediated induction of cell proliferation and differentiation and the proepithelin-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of proepithelin on NF-kappa B activation. Finally, using siRNA and antisense strategies, we demonstrated that endogenously produced proepithelin by chondrocytes is important for chondrocyte growth in serum-deprived conditions. These results support the hypothesis that the induction of NF-kappa B activity of in growth plate chondrocytes is critical in proepithelin-mediated growth plate chondrogenesis and longitudinal bone growth.