A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies. Institutional Repository Document uri icon

abstract

  • AbstractCanonical Wnt signaling is an osteo-inductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signaling and thus inhibits osteogenesis. To examine a potential osteo-inhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in pediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumor periphery and in vitro Dkk-1 and RANKL are co-expressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduces osteogenesis by human mesenchymal cells and by immuno-depletion of Dkk-1, or by adding a GSK3[beta] inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumors was similar to the human tumor biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in osteosarcoma. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumor probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immuno-depletion of Dkk-1 or administration of GSK3[beta] inhibitors could represent an adjunct therapy for this disease.

author list (cited authors)

  • Gregory, C., Lee, N., Smolarz, A., Olson, S., David, O., Reiser, J., ... Horwitz, E.

citation count

  • 0

complete list of authors

  • Gregory, Carl||Lee, Narae||Smolarz, Angela||Olson, Scott||David, Odile||Reiser, Jacob||Kutner, Robert||Daw, Najat||Prockop, Darwin||Horwitz, Edwin

Book Title

  • Nature Precedings

publication date

  • June 2007