title: The effect of TNFα secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells.
abstract: 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, TNFα 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 TNFα 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 TNFα via induction of SOST in osteprogenitor cells.
authors.affiliation: Infectious Disease Medical Research Center & Department of Pharmacology, College of Medicine, Hallym University, Chucheon, Gangwon-do 200-702, Republic of Korea.
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Lee
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Sharma
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Choi
authors.forename: Jun-Sub
authors.initials: JS
authors.lastname: Jung
authors.forename: Jun-Dong
authors.initials: JD
authors.lastname: Chang
authors.forename: Seonghun
authors.initials: S
authors.lastname: Park
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Salvati
authors.forename: Edward P
authors.initials: EP
authors.lastname: Purdue
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Song
authors.forename: Ju-Suk
authors.initials: JS
authors.lastname: Nam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014025:Titanium / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines; D006023:Glycoproteins; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; C486030:Sost protein, mouse; D014409:Tumor Necrosis Factor-alpha; D060509:Wnt3A Protein; D014025:Titanium; D000469:Alkaline Phosphatase