Pharmaceutical inhibition of glycogen synthetase kinase-3β reduces multiple myeloma-induced bone disease in a novel murine plasmacytoma xenograft model.
Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow. MM is incurable with approximately 100 000 patients currently in the United States and 20 000 new cases diagnosed yearly. The malignancy causes displacement of hematopoiesis and formation of osteolytic bone lesions also known as myeloma bone disease (MBD). At diagnosis, 79% of patients suffer from MBD associated with severe pain and increased mortality. Wnt inhibitors secreted by MM cells inhibit osteogenesis and promote osteoclastogenesis, therefore rapid targeting of Wnt inhibitors is necessary to prevent potentially irreversible effects on the stroma, which could lead to incurable MBD. Inhibition of glycogen synthetase kinase-3β (GSK3β) causes accelerated Wnt signaling and enhanced osteogenesis in mesenchymal stem/progenitor cells, irrespective of the extracellular concentration of Wnt inhibitors. Our primary goal of this study was to evaluate a GSK3β inhibitor (6-bromoindirubin-3'-oxime BIO) for amelioration of bone destruction in a murine model of MBD. When measured using histomorphometry, peritumoral BIO administration improved bone quality at the bone-tumor interface and, surprisingly, increased histologically apparent tumor necrosis. Furthermore, in vitro assays demonstrated a proapoptotic effect on numerous MM cell lines. These preliminary data suggest that pharmaceutical GSK3β inhibition may improve bone quality in myeloma and other malignant bone diseases.
Center for Gene Therapy, and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA.
W Grady
WG
Gunn
Ulf
U
Krause
Narae
N
Lee
Carl A
CA
Gregory
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001847:Bone Diseases / Q000201:enzymology / Q000209:etiology* / Q000517:prevention & control*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D010091:Oximes / Q000494:pharmacology*; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D051153:Wnt Proteins / Q000378:metabolism
C483321:6-bromoindirubin-3'-oxime; D015415:Biomarkers; D007211:Indoles; D010091:Oximes; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000469:Alkaline Phosphatase