A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies.
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.
Lee
N
N
Department of Medicine, Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Smolarz
A J
AJ
Olson
S
S
David
O
O
Reiser
J
J
Kutner
R
R
Daw
N C
NC
Prockop
D J
DJ
Horwitz
E M
EM
Gregory
C A
CA
D000293:Adolescent; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D002454:Cell Differentiation / Q000187:drug effects; D002648:Child; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000097:blood / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D012516:Osteosarcoma / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D011237:Predictive Value of Tests; D053245:RANK Ligand / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; C501126:DKK1 protein, human; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000469:Alkaline Phosphatase