Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation
Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation
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DOI：
10.1182/blood-2004-12-4986
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发表时间：
2005-10-01
期刊：
影响因子：
20.3
通讯作者：
Rizzoli, V
中科院分区：
文献类型：
--
作者：
Giuliani, N;Colla, S;Rizzoli, V
骨形成减少有助于多发性骨髓瘤（MM）患者骨病变的发展。在这项研究中，我们研究了骨髓瘤细胞对成骨细胞形成和分化的影响，以及关键的成骨细胞转录因子RUNX2/CBFA1（Runt相关转录因子2/核心结合因子Runt结构域a亚基1）在MM成骨细胞生成抑制中的潜在作用。我们发现，人骨髓瘤细胞抑制骨髓（BM）培养物中人成骨细胞祖细胞的形成。此外，在与骨髓瘤细胞共培养中观察到人前成骨细胞对骨钙素、碱性磷酸酶、胶原I mRNA、蛋白表达和RUNX2/CBFA 1活性的抑制作用。在细胞与细胞接触的条件下，与没有接触的条件相比，抑制作用更明显，并且涉及极晚期抗原4（VLA-4）整联蛋白系统。在筛选的可溶性成骨细胞抑制剂中，我们显示了白细胞介素-7（IL-7）在共培养的人骨髓瘤细胞对成骨细胞形成和RUNX2/CBFA 1活性的抑制作用中的潜在贡献。最后，我们的体外研究结果得到了体内研究的支持，与没有骨病变的MM患者相比，有溶骨性病变的MM患者的BM活检中Runx2/Cbfa 1阳性细胞数量显著减少，这表明RUNX2/CBFA 1在MM骨形成减少中起关键作用。
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 a 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.