摘要：

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.sup.+][CD31.sup.-][CD34.sup.-] 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.sup.+] 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. INTRODUCTION MULTIPLE MYELOMA (MM) is a plasma cell malignancy. One of the major clinical features of MM is bone disease (1,2), with bone destruction characterized by an unbalanced bone remodeling with an increased bone resorption and a decreased bone formation (3). The increased bone resorption related to the stimulation of osteoclast (OCL) recruitment and activity has been under intensive investigation (4,5). Two molecules belonging to the tumor necrosis factor (TNF) receptor-ligand superfamily, the receptor activator of nuclear factor-[kappa]B ligand (RANKL) and its soluble antagonist, osteoprotegerin (OPG), were reported to play a critical role in the regulation of bone resorption (6). In contrast to the intensive research on OCLs, the mechanism of the decreased osteoblast (OBL) formation and activity remains poorly understood. Recently, the canonical Wingless-type (Wnt) signaling pathway has been shown to be an important signaling pathway in the mechanism of MM bone lesions (7). Dickkopf1 (DKK1), secreted Frizzledrelated protein2 (sFRP-2), and some other soluble Wnt inhibitors secreted by myeloma cells suppressed bone formation in MM (8, 9). Runt-related protein 2 (Runx2)/core binding factor 1 (Cbfa1), a member of the runt homology domain transcription factor family, is essential for osteoblast differentiation (10-13). Giuliani et al. reported that myeloma cells suppressed Runx2/Cbfa1 activity in human bone marrow (BM) osteoblast progenitors and inhibited osteoblast formation and differentiation through the cell-tocell contact and in part secreting interleukin-7 (IL-7) (14). A Runx2/Cbfa1 inhibitor, TNF-[alpha], was reported to increase significantly in the myeloma patients with severe osteolytic lesions compared with myeloma patients without skeletal involvement or patients with monoclonal gammopathy of undetermined significance (MGUS) (15) and has a central role in bone pathophysiology (16). Mesenchymal stem cells (MSCs), which originate from mesoblasts, have multipotential differentiation ability, especially the potential to differentiate into lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow...

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