The effect of TNF伪 secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells

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• 作者：Sang-Soo Lee^a ; ^b ; ¹ ; Ashish R. Sharma^a ; ^b ; ¹ ; Byung-Soo Choi^a ; ^b ; Jun-Sub Jung^a ; Jun-Dong Chang^b ; Seonghun Park^b ; ^c ; Eduardo A. Salvati^d ; Edward P. Purdue^d ; Dong-Keun Song^a ; Ju-Suk Nam^a ; ^b ; ^{jsnam88@hallym.ac.kr}
• 关键词：Particle ; TNF伪 ; Osteolysis ; WNT ; BMP ; SOST
• 刊名：Biomaterials
• 出版年：2012
• 期刊代码：7_01429612
• 类别：ms
• 出版时间：June, 2012
• 卷：33
• 期：17
• 页码：4251-4263
• 文件大小：1682 K

摘要

Wear particles are the major cause of osteolysis associated with failure of implant following total joint replacement. During this pathologic process, activated macrophages mediate inflammatory responses to increase osteoclastogenesis, leading to enhanced bone resorption. In osteolysis caused by wear particles, osteoprogenitors present along with macrophages at the implant interface may play significant roles in bone regeneration and implant osteointegration. Although the direct effects of wear particles on osteoblasts have been addressed recently, the role of activated macrophages in regulation of osteogenic activity of osteoblasts has scarcely been studied. In the present study, we examined the molecular communication between macrophages and osteoprogenitor cells that may explain the effect of wear particles on impaired bone forming activity in inflammatory bone diseases. It has been demonstrated that conditioned medium of macrophages challenged with titanium particles (Ti CM) suppresses early and late differentiation markers of osteoprogenitors, including alkaline phosphatase (ALP) activity, collagen synthesis, matrix mineralization and expression of osteocalcin and Runx2. Moreover, bone forming signals such as WNT and BMP signaling pathways were inhibited by Ti CM. Interestingly, TNF伪 was identified as a predominant factor in Ti CM to suppress osteogenic activity as well as WNT and BMP signaling activity. Furthermore, Ti CM or TNF伪 induces the expression of sclerostin (SOST) which is able to inhibit WNT and BMP signaling pathways. It was determined that over-expression of SOST suppressed ALP activity, whereas the inhibition of SOST by siRNA partially restored the effect of Ti CM on ALP activity. This study highlights the role of activated macrophages in regulation of impaired osteogenic activity seen in inflammatory conditions and provides a potential mechanism for autocrine regulation of WNT and BMP signaling mediated by TNF伪 via induction of SOST in osteprogenitor cells.