Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation.
Decreased bone formation contributes to the development of bone lesions in multiple myeloma (MM) patients. In this study, we have investigated the effects of myeloma cells on osteoblast formation and differentiation and the potential role of the critical osteoblast transcription factor RUNX2/CBFA1 (Runt-related transcription factor 2/core-binding factor Runt domain alpha subunit 1) in the inhibition of osteoblastogenesis in MM. We found that human myeloma cells suppress the formation of human osteoblast progenitors in bone marrow (BM) cultures. Moreover, an inhibitory effect on osteocalcin, alkaline phosphatase, collagen I mRNA, protein expression, and RUNX2/CBFA1 activity by human preosteoblastic cells was observed in cocultures with myeloma cells. The inhibitory effect was more pronounced in the cell-to-cell contact conditions compared with those without the contact and involved the very late antigen 4 (VLA-4) integrin system. Among the soluble osteoblast inhibitors screened, we show the potential contribution of interleukin-7 (IL-7) in the inhibitory effect on osteoblast formation and RUNX2/CBFA1 activity by human myeloma cells in coculture. Finally, our in vitro results were supported in vivo by the finding of a significant reduction in the number of Runx2/Cbfa1-positive cells in the BM biopsies of patients with MM who had osteolytic lesions compared with those who did not have bone lesions, suggesting the critical involvement of RUNX2/CBFA1 in the decreased bone formation in MM.
Giuliani
Nicola
N
Laboratory of Hematology, Hematology and Bone Marrow Transplantation (BMT) Center, Department of Internal Medicine and Biomedical Science, University of Parma, Parma, Italy. nicola.giuliani@unipr.it
Colla
Simona
S
Morandi
Francesca
F
Lazzaretti
Mirca
M
Sala
Roberto
R
Bonomini
Sabrina
S
Grano
Maria
M
Colucci
Silvia
S
Svaldi
Mirija
M
Rizzoli
Vittorio
V
D000469:Alkaline Phosphatase / Q000378:metabolism; D017209:Apoptosis; D001706:Biopsy; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*
D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; D039041:Integrin alpha4beta1; D015851:Interleukin-7; C493716:Runx2 protein, mouse; D015675:Osteocalcin; D012313:RNA; D003094:Collagen; D000469:Alkaline Phosphatase