Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2
Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2
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DOI：
10.1182/blood-2004-12-4940
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发表时间：
2005-11-01
期刊：
影响因子：
20.3
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
--
作者：
Oshima, T;Abe, M;Matsumoto, T
多发性骨髓瘤（MM）发展为破坏性骨破坏，伴有骨吸收增强和骨形成抑制。相反，增强破骨细胞生成，很少有人知道的机制受损的骨形成MM。因为一个典型的无翼型（Wnt）信号通路最近已被证明在成骨细胞分化中发挥重要作用，我们研究了MM细胞是否影响一个典型的Wnt通路抑制骨形成。来自RPM 18226和U266 MM细胞系和原代MM细胞的条件培养基抑制骨形态发生蛋白2（BMP-2）诱导的成骨细胞中的体外矿化以及碱性磷酸酶活性。这些细胞系组成性地产生可溶性Wnt抑制剂，分泌卷曲相关蛋白2（sFRP-2），但在蛋白水平上不产生其他Wnt抑制剂，包括sFRP-1、sFRP-3和dickkopf 1（DKK-1）。来自患有晚期骨破坏性病变的患者的大多数MM细胞也表达sFRP-2。此外，外源性sFRP-2抑制BMP-2诱导的成骨细胞分化，sFRP-2的免疫耗竭显著恢复体外矿化结节形成，表明MM细胞衍生的sFRP-2在MM对骨形成的损害中起主要作用。因此，除了增强骨质溶解外，MM细胞还至少部分地通过分泌sFRP-2抑制经典Wnt途径来抑制骨形成。
Multiple myeloma (MM) develops devastating bone destruction with enhanced bone resorption and suppressed bone formation. In contrast to enhanced osteoclastogenesis, little is known about the mechanism of impaired bone formation in MM. Because a canonical Wingless-type (Wnt) signaling pathway has recently been shown to play an important role in osteoblast differentiation, we examined whether MM cells affect a canonical Wnt pathway to suppress bone formation. Conditioned media from RPM18226 and U266 MM cell lines and primary MM cells suppressed in vitro mineralization as well as alkaline phosphatase activity in osteoblasts induced by bone morphogenetic protein 2 (BMP-2). These cell lines constitutively produced a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced bone destructive lesions also expressed sFRP-2. Furthermore, exogenous sFRP-2 suppressed osteoblast differentiation induced by BMP-2, and immunodepletion of sFRP-2 significantly restored mineralized nodule formation in vitro, suggesting a predominant role for MM cell-derived sFRP-2 in the impairment of bone formation by MM. Thus, in addition to enhanced osteolysis, MM cells also suppress bone formation at least in part through an inhibition of the canonical Wnt pathway by secreting sFRP-2.