Elevated tumor necrosis factor-alpha suppresses TAZ expression and impairs osteogenic potential of Flk-1+ mesenchymal stem cells in patients with multiple myeloma.
One of the clinical features of multiple myeloma (MM) is the occurrence of skeletal events, which are characterized by increased bone resorption and decreased bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because TAZ, a Runx2/Cbfa1 transcriptional co-activator, has recently been shown to modulate mesenchymal stem cell (MSC) differentiation in favor of osteoblast differentiation, we investigated whether the regulation of TAZ expression played a role in the decreased bone formation of MM. We isolated and purified Flk-1(+)CD31(-)CD34(-) cells with MSC characters from bone marrow (BM) of myeloma patients and healthy donors. We found the osteogenic potential of the MSCs from myeloma patients decreased significantly, and TAZ expression of these cells was lower than that of healthy donors. Human myeloma cell lines (HMCLs) and CD138(+) myeloma cells (MCs) from myeloma patients inhibited osteogenesis of the MSCs from healthy volunteers, which were accompanied by a reduced TAZ expression and elevated TNF-alpha concentration in the supernatant of co-culture systems. The repressed osteogenesis and TAZ expression were both partially restored by neutralization of TNF-alpha. Thus, the decreased osteogenic potential of MSCs of myeloma patients was in part due to TNF-alpha suppressed TAZ expression.
Li
Bingzong
B
Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
Shi
Mingxia
M
Li
Jing
J
Zhang
Hongbing
H
Chen
Bin
B
Chen
Lei
L
Gao
Weibo
W
Giuliani
Nicola
N
Zhao
Robert Chunhua
RC
D000217:Acyltransferases; D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007621:Karyotyping; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology* / Q000502:physiology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010006:Osteoblasts / Q000166:cytology / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D011506:Proteins / Q000235:genetics*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D011506:Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2