Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells
Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells
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DOI：
10.1038/leu.2012.190
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发表时间：
2013-02-01
期刊：
影响因子：
11.4
通讯作者：
Giuliani, N.
中科院分区：
文献类型：
--
作者：
Bolzoni, M.;Donofrio, G.;Giuliani, N.
多发性骨髓瘤（MM）的特征在于人骨髓间充质干细胞（hMSCs）的成骨分化受损。经典Wnt信号传导对于骨形成的调节至关重要，然而，最近的证据表明非经典Wnt激动剂Wnt 5a通过其共受体Ror 2刺激人成骨细胞生成。MM细胞对非经典Wnt信号传导的影响以及该途径的激活对MM诱导的成骨细胞耗竭的影响尚不清楚，并在本研究中进行了研究。我们发现骨髓hMSCs向骨祖细胞（PreOB）的成骨分化显著增加了Ror 2的表达，并且MM细胞通过抑制非经典Wnt 5a信号传导来抑制共培养中PreOB的Ror 2表达。通过Wnt 5a处理和通过慢病毒载体过表达Wnt 5或Ror 2来激活hMSCs中的非经典Wnt途径，增加了hMSCs的成骨分化，并减弱了共培养中MM的抑制作用。一致地，通过特异性小干扰RNA抑制Wnt 5a降低了hMSC成骨标志物的表达。我们的研究结果表明，Wnt 5a/Ror 2通路参与MM诱导的骨疾病的病理生理学，并且hMSC中非经典Wnt 5a/Ror 2通路的激活增加了成骨分化，并可能抵消MM细胞的抑制作用。白血病（2013）27，451-463; doi：10.1038/leu.2012.190
Multiple nnyeloma (MM) is characterized by the impaired osteogenic differentiation of human nnesenchymal stromal cells (hMSCs). Canonical Wnt signaling is critical for the regulation of bone formation, however, recent evidence suggests that the non-canonical Wnt agonist Wnt5a stimulates human osteoblastogenesis through its co-receptor Ror2. The effects of MM cells on non-canonical Wnt signaling and the effect of the activation of this pathway on MM-induced osteoblast exhaustion are not known and were investigated in this study. We found that the osteogenic differentiation of bone marrow hMSCs toward osteoprogenitor cells (PreOB) significantly increased Ror2 expression, and that MM cells inhibit Ror2 expression by PreOB in co-culture by inhibiting the non-canonical Wnt5a signaling. The activation of the non-canonical Wnt pathway in hMSCs by means of Wnt5a treatment and the overexpression of Wnt5 or Ror2 by lentiviral vectors increased the osteogenic differentiation of hMSCs and blunted the inhibitory effect of MM in co-culture. Consistently, Wnt5a inhibition by specific small interfering RNA reduced the hMSC expression of osteogenic markers. Our findings demonstrate that the Wnt5a/Ror2 pathway is involved in the pathophysiology of MM-induced bone disease and that the activation of the non-canonical Wnt5a/Ror2 pathway in hMSCs increases osteogenic differentiation and may counterbalance the inhibitory effect of MM cells. Leukemia (2013) 27, 451-463; doi:10.1038/leu.2012.190