Li Xin, Pennisi Angela, Yaccoby Shmuel
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Blood. 2008 Jul 1;112(1):159-68. doi: 10.1182/blood-2007-11-124164. Epub 2008 Apr 24.
Building on our previous report that osteoblasts and increased bone formation have a negative impact on myeloma cell growth in a subset of patients, we investigated the role of decorin, the main small leucine-rich proteoglycan (SLRP) expressed and produced by osteoblasts, in the antimyeloma effects of osteoblasts. In coculture experiments with osteoblasts, primary myeloma cell survival was significantly higher when decorin expression in osteoblasts was knocked down by short-hairpin RNA. Coculture experiments of myeloma cells and supporting osteoclasts in the presence of osteoblast-conditioned medium showed reduced myeloma cell survival, an effect that was attenuated by decorin-neutralizing antibody. Decorin overexpression in mesenchymal stem cells or use of recombinant decorin in coculture with osteoclasts reduced the ability of osteoclasts to support primary myeloma cell survival. The antimyeloma effect of decorin involved direct induction of apoptosis and activation of p21(WAF). Decorin also inhibited myeloma cell-induced tube formation and osteoclast differentiation. Decorin expression was insignificantly lower in patients' than donors' osteoblasts and slightly increased by bortezomib. Certain SLRPs are involved in the antimyeloma effect of osteoblasts directly and indirectly through inhibition of angiogenesis and osteoclastogenesis; therefore, increasing endogenous or exogenous SLRPs in myelomatous bone may help control myeloma.
基于我们之前的报告，即成骨细胞和骨形成增加对一部分患者的骨髓瘤细胞生长有负面影响，我们研究了核心蛋白聚糖（decorin）在成骨细胞抗骨髓瘤作用中的角色，核心蛋白聚糖是成骨细胞表达和产生的主要富含亮氨酸的小分子蛋白聚糖（SLRP）。在与成骨细胞的共培养实验中，当通过短发夹RNA敲低成骨细胞中的核心蛋白聚糖表达时，原发性骨髓瘤细胞的存活率显著更高。在成骨细胞条件培养基存在的情况下，骨髓瘤细胞与支持性破骨细胞的共培养实验显示骨髓瘤细胞存活率降低，而核心蛋白聚糖中和抗体可减弱这一效应。间充质干细胞中核心蛋白聚糖的过表达或在与破骨细胞共培养中使用重组核心蛋白聚糖可降低破骨细胞支持原发性骨髓瘤细胞存活的能力。核心蛋白聚糖的抗骨髓瘤作用涉及直接诱导细胞凋亡和激活p21（WAF）。核心蛋白聚糖还抑制骨髓瘤细胞诱导的血管生成和破骨细胞分化。患者成骨细胞中的核心蛋白聚糖表达比供体成骨细胞略低，且硼替佐米可使其略有增加。某些SLRP通过抑制血管生成和破骨细胞生成直接和间接参与成骨细胞的抗骨髓瘤作用；因此，增加骨髓瘤骨中的内源性或外源性SLRP可能有助于控制骨髓瘤。
