WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity.
WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity.
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DOI：
10.1002/jbmr.205
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发表时间：
2011-01
影响因子：
6.2
通讯作者：
Young, Marian F.
中科院分区：
文献类型：
--
作者：
Ono, Mitsuaki;Inkson, Colette A.;Kilts, Tina M.;Young, Marian F.
Wnt诱导分泌蛋白1（WISP - 1/CCN4）是CCN家族的成员，在骨骼组织以及体外诱导分化的骨祖细胞中高度表达。为了确定WISP - 1在成骨过程中的功能，在有或无骨形态发生蛋白2（BMP - 2）腺病毒（adBMP - 2）存在的情况下，用WISP - 1腺病毒（adWISP - 1）转导成骨骨髓基质细胞（BMSCs）。WISP - 1的过表达增强了BMP - 2引导BMSCs向成骨分化的能力，并且似乎是通过刺激Smad - 1/5/8磷酸化和激活来发挥作用。使用转导了WISP - 1、BMP - 2或两者的BMSCs进行异位成骨实验，在体内也显示了WISP - 1增强BMP - 2活性的能力。当BMSCs被含有人类WISP1 shRNA的慢病毒感染时，它们在体内形成的骨量减少，并且对BMP - 2的反应性降低，这证实了WISP - 1和BMP - 2具有功能性相互作用。免疫沉淀（IP）和蛋白质印迹分析表明，WISP - 1直接与BMP - 2结合，并且表明WISP - 1以剂量依赖的方式增加BMP - 2与人类BMSCs的结合。为了了解WISP - 1如何增强BMP - 2信号传导，分析了WISP - 1对整合素表达的影响。WISP - 1诱导α5 -整合素的mRNA和蛋白质水平升高，并且进一步发现与之结合。抗体阻断实验表明，用抗整合素α5β1抗体处理可完全中和由WISP - 1增强的BMP - 2与BMSCs的结合。初步研究以及在前成骨细胞中过表达人类WISP - 1的转基因小鼠的使用显示，与野生型对照相比，其骨矿物质密度（BMD）、小梁厚度和骨体积（BV/TV）增加，这支持了使用人类骨祖细胞所得到的观察结果，即WISP - 1在体内对成骨具有积极影响。总之，这些研究首次表明，WISP - 1对骨细胞分化和功能具有积极影响，并且可能通过增强BMP - 2的作用来增加成骨，其机制可能涉及与整合素α5β1的结合。© 2011美国骨与矿物质研究学会
Wnt-induced secreted protein 1 (WISP-1/CCN4) is a member of the CCN family that is highly expressed in skeletal tissue and in osteoprogenitor cells induced to differentiate in vitro. To determine the function of WISP-1 during osteogeneis, osteogenic bone marrow stromal cells (BMSCs) were transduced with WISP-1 adenovirus (adWISP-1) in the presence or absence of bone morphogenetic protein 2 (BMP-2) adenovirus (adBMP-2). WISP-1 overexpression enhanced the ability of BMP-2 to direct BMSCs toward osteogenic differentiation and appeared to work by stimulating Smad-1/5/8 phosphorylation and activation. The ability of WISP-1 to enhance BMP-2 activity also was shown in vivo using an ectopic osteogenesis assay with BMSCs transduced with WISP-1, BMP-2, or both. When BMSCs were infected with lentivirus containing human WISP1 shRNA, they formed less bone in vivo and were less responsive to BMP-2, confirming that WISP-1 and BMP-2 have a functional interaction. Immunoprecipitation (IP) and Western blot analysis showed that WISP-1 bound directly to BMP-2 and showed that WISP-1 increased BMP-2 binding to hBMSCs in a dose-dependent fashion. To understand how WISP-1 enhanced BMP-2 signaling, the influence of WISP-1 on integrin expression was analyzed. WISP-1 induced the mRNA and protein levels of α5 -integrin and, further, was found to bind to it. Antibody-blocking experiments showed that the BMP-2 binding to BMSCs that was enhanced by WISP-1 was completely neutralized by treatment with anti-integrin α5 β1 antibody. Pilot studies and the use of transgenic mice that overexpressed human WISP-1 in preosteoblasts had increased bone mineral density (BMD), trabecular thickness, and bone volume (BV/TV) over wild-type controls, supporting observations using human osteoprogenitors that WISP-1 has a positive influence on osteogenesis in vivo. In conclusion, these studies show, for the first time, that WISP-1 has a positive influence on bone cell differentiation and function and may work by enhancing the effects of BMP-2 to increase osteogenesis through a mechanism potentially involving binding to integrin α5 β1 . © 2011 American Society for Bone and Mineral Research.
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