A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

• Published in: British journal of cancer Vol. 97; no. 11; pp. 1552 - 1559
• Main Authors: Lee, N, Smolarz, A J, Olson, S, David, O, Reiser, J, Kutner, R, Daw, N C, Prockop, D J, Horwitz, E M, Gregory, C A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.12.2007
• Subjects: Adolescent; Alkaline Phosphatase - metabolism; Animals; Bone cancer; Bone marrow; Bone Neoplasms - diagnosis; Bone Neoplasms - pathology; Bone Neoplasms - therapy; Cancer research; Cell Differentiation - drug effects; Child; Culture Media, Conditioned - pharmacology; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; Health sciences; Hospitals; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - blood; Intercellular Signaling Peptides and Proteins - pharmacology; Intercellular Signaling Peptides and Proteins - physiology; Kinases; Medical research; Mice; Mice, Nude; Molecular Diagnostics; Multiple myeloma; Neoplasms, Experimental - blood; Neoplasms, Experimental - pathology; Osteogenesis - drug effects; Osteosarcoma - diagnosis; Osteosarcoma - pathology; Osteosarcoma - therapy; Pathogenesis; Pediatrics; Predictive Value of Tests; RANK Ligand - metabolism; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors; United States > US
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6604069

Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric 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 tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3beta inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour 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 OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour 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, immunodepletion of Dkk-1 or administration of GSK3beta inhibitors could represent an adjunct therapy for this disease.