{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T01:08:29Z","timestamp":1780103309108,"version":"3.54.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Engineered biomaterials are envisioned to replace, augment, or interact with living tissues for improving the functional deformities associated with end-stage joint pathologies. Unfortunately, wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NF\u03baB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of Rankl in the conditioned medium collected from Ti particle\u2013stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1\u03b1, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particle\u2013treated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris\u2013stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis.<\/jats:p>","DOI":"10.3389\/fmolb.2021.666295","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T04:31:19Z","timestamp":1624422679000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Sclerostin-Mediated Impaired Osteogenesis by Fibroblast-Like Synoviocytes in the Particle-Induced Osteolysis Model"],"prefix":"10.3389","volume":"8","author":[{"given":"Supriya","family":"Jagga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish Ranjan","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Hee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Suk","family":"Nam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Soo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"B1","unstructured":"FDA Approves EVENITY\u2122 (Romosozumab-aqqg) for the Treatment of Osteoporosis in Postmenopausal Women at High Risk for Fracture2020"},{"key":"B2","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1002\/1097-4644(20010315)80:4<532::aid-jcb1007>3.0.co;2-b","article-title":"An Optimized Method for the Chemiluminescent Detection of Alkaline Phosphatase Levels during Osteodifferentiation by Bone Morphogenetic Protein 2","volume":"80","author":"Blum","year":"2001","journal-title":"J. Cel. Biochem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"18","DOI":"10.14573\/altex.1804161","article-title":"A Three-Dimensional Model to Study Human Synovial Pathology","volume":"36","author":"Broeren","year":"2019","journal-title":"ALTEX"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/s0736-0266(03)00153-0","article-title":"PGE2 and IL-6 Production by Fibroblasts in Response to Titanium Wear Debris Particles Is Mediated through a Cox-2 Dependent Pathway","volume":"22","author":"Bukata","year":"2004","journal-title":"J. Orthop. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"30399","DOI":"10.1074\/jbc.m113.469973","article-title":"Critical Role of AKT Protein in Myeloma-Induced Osteoclast Formation and Osteolysis","volume":"288","author":"Cao","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.ydbio.2010.03.021","article-title":"Genetic Evidence that SOST Inhibits WNT Signaling in the Limb","volume":"342","author":"Collette","year":"2010","journal-title":"Dev. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"11","DOI":"10.4248\/BR201301003","article-title":"Osteoclasts: New Insights","volume":"1","author":"Feng","year":"2013","journal-title":"Bone Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1055\/s-0034-1398375","article-title":"Wear and Loosening in Total Knee Arthroplasty: a Quick Review","volume":"28","author":"Fraser","year":"2015","journal-title":"J. Knee Surg."},{"key":"B9","doi-asserted-by":"publisher","first-page":"231","DOI":"10.5301\/hip.2011.7977","article-title":"Wear Debris Stimulates Bone-Resorbing Factor Expression in the Fibroblasts and Osteoblasts","volume":"21","author":"Fujii","year":"2011","journal-title":"HIP Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1177\/1753425912451779","article-title":"Particle Disease: Biologic Mechanisms of Periprosthetic Osteolysis in Total Hip Arthroplasty","volume":"19","author":"Gallo","year":"2013","journal-title":"Innate Immun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1159\/000047893","article-title":"Impaired Intramembranous Bone Formation during Bone Repair in the Absence of Tumor Necrosis Factor-Alpha Signaling","volume":"169","author":"Gerstenfeld","year":"2001","journal-title":"Cells Tissues Organs"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2106\/jbjs.rvw.15.00081","article-title":"Osteolysis Complicating Total Knee Arthroplasty","volume":"4","author":"Gilbert","year":"2016","journal-title":"JBJS Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.1016\/s0142-9612(98)00140-9","article-title":"Polyethylene Particles of a 'critical Size' Are Necessary for the Induction of Cytokines by Macrophages In Vitro","volume":"19","author":"Green","year":"1998","journal-title":"Biomaterials"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s13258-019-00845-3","article-title":"Influence of Single Nucleotide Polymorphisms (SNPs) in Genetic Susceptibility towards Periprosthetic Osteolysis","volume":"41","author":"Jagga","year":"2019","journal-title":"Genes Genom."},{"key":"B15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1111\/j.1600-0714.1988.tb01515.x","article-title":"Osteoclast Activating Factor Is Now Interleukin-1 Beta: Historical Perspective and Biological Implications","volume":"17","author":"Jandinski","year":"1988","journal-title":"J. Oral. Pathol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1007\/s00018-016-2425-5","article-title":"Wnt Signaling and Cellular Metabolism in Osteoblasts","volume":"74","author":"Karner","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3221","DOI":"10.1002\/art.22134","article-title":"The Role of Fibroblasts and Fibroblast-Derived Factors in Periprosthetic Osteolysis","volume":"54","author":"Koreny","year":"2006","journal-title":"Arthritis Rheum."},{"key":"B18","doi-asserted-by":"publisher","first-page":"41614","DOI":"10.1074\/jbc.m110.153890","article-title":"Distinct Modes of Inhibition by Sclerostin on Bone Morphogenetic Protein and Wnt Signaling Pathways*","volume":"285","author":"Krause","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4251","DOI":"10.1016\/j.biomaterials.2012.03.005","article-title":"The Effect of TNF\u03b1 Secreted from Macrophages Activated by Titanium Particles on Osteogenic Activity Regulated by WNT\/BMP Signaling in Osteoprogenitor Cells","volume":"33","author":"Lee","year":"2012","journal-title":"Biomaterials"},{"key":"B20","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1111\/joim.12368","article-title":"The WNT System: Background and its Role in Bone","volume":"277","author":"Lerner","year":"2015","journal-title":"J. Intern. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"19883","DOI":"10.1074\/jbc.m413274200","article-title":"Sclerostin Binds to LRP5\/6 and Antagonizes Canonical Wnt Signaling","volume":"280","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"4012","DOI":"10.1002\/art.37697","article-title":"Sclerostin Antibody Prevents Particle-Induced Implant Loosening by Stimulating Bone Formation and Inhibiting Bone Resorption in a Rat Model","volume":"64","author":"Liu","year":"2012","journal-title":"Arthritis Rheum."},{"key":"B23","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/ar300","article-title":"NF-kappa B in Rheumatoid Arthritis: a Pivotal Regulator of Inflammation, Hyperplasia, and Tissue Destruction","volume":"3","author":"Makarov","year":"2001","journal-title":"Arthritis Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.sbi.2014.10.003","article-title":"Extracellular Modulators of Wnt Signalling","volume":"29","author":"Malinauskas","year":"2014","journal-title":"Curr. Opin. Struct. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1172\/jci93356","article-title":"Inflammatory Osteolysis: a Conspiracy against Bone","volume":"127","author":"Mbalaviele","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B26","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s00402-007-0450-4","article-title":"Results of Bilateral Combined Hip and Knee Arthroplasty in Very Young Patients with Juvenile Rheumatoid Arthritis","volume":"128","author":"Mulhall","year":"2008","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"B27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/bs.vh.2015.06.004","article-title":"The Bone Morphogenetic Proteins and Their Antagonists","volume":"99","author":"Mulloy","year":"2015","journal-title":"Vitam. Horm."},{"key":"B28","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1038\/nri3073","article-title":"Protective and Pathogenic Functions of Macrophage Subsets","volume":"11","author":"Murray","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/s1875-5364(17)30084-5","article-title":"Anti-inflammatory Effects of Traditional Mixed Extract of Medicinal Herbs (MEMH) on Monosodium Urate crystal-induced Gouty Arthritis","volume":"15","author":"Nam","year":"","journal-title":"Chin. J. Nat. Medicines"},{"key":"B30","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1002\/jbm.a.36004","article-title":"Suppression of Osteogenic Activity by Regulation of WNT and BMP Signaling during Titanium Particle Induced Osteolysis","volume":"105","author":"Nam","year":"","journal-title":"J. Biomed. Mater. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1186\/ar113","article-title":"Fibroblast Biology. Role of Synovial Fibroblasts in the Pathogenesis of Rheumatoid Arthritis","volume":"2","author":"Pap","year":"2000","journal-title":"Arthritis Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"031007","DOI":"10.1116\/1.4886255","article-title":"Role of Hyaluronic Acid and Phospholipid in the Lubrication of a Cobalt-Chromium Head for Total Hip Arthroplasty","volume":"9","author":"Park","year":"2014","journal-title":"Biointerphases"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1093\/rheumatology\/34.12.1127","article-title":"Analysis of Cell Types and Mediator Production from Tissues Around Loosening Joint Implants","volume":"34","author":"Perry","year":"1995","journal-title":"Rheumatology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s11420-006-9003-6","article-title":"The central Role of Wear Debris in Periprosthetic Osteolysis","volume":"2","author":"Purdue","year":"2006","journal-title":"HSS J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/978-1-59745-401-8_24","article-title":"Acquisition, Culture, and Phenotyping of Synovial Fibroblasts","volume":"135","author":"Rosengren","year":"2007","journal-title":"Methods Mol. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.bone.2016.10.009","article-title":"Transcriptional Control of Sost in Bone","volume":"96","author":"Sebastian","year":"2017","journal-title":"Bone"},{"key":"B37","doi-asserted-by":"publisher","first-page":"19805","DOI":"10.3390\/ijms141019805","article-title":"Interplay between Cartilage and Subchondral Bone Contributing to Pathogenesis of Osteoarthritis","volume":"14","author":"Sharma","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.3390\/ma13163628","article-title":"Fibroblast-Like-Synoviocytes Mediate Secretion of Pro-inflammatory Cytokines via ERK and JNK MAPKs in Ti-Particle-Induced Osteolysis","volume":"13","author":"Sharma","year":"2020","journal-title":"Materials (Basel)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"847529","DOI":"10.1155\/2015\/847529","article-title":"Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway","volume":"2015","author":"Sharma","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"B40","doi-asserted-by":"publisher","first-page":"179","DOI":"10.5371\/hp.2019.31.4.179","article-title":"Total Hip Arthroplasty: Past, Present, and Future. What Has Been Achieved?","volume":"31","author":"Shon","year":"2019","journal-title":"Hip. Pelvis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3390\/ijms18030499","article-title":"Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies","volume":"18","author":"Veronesi","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"330ra35","DOI":"10.1126\/scitranslmed.aac4351","article-title":"Sclerostin Inhibition Promotes TNF-dependent Inflammatory Joint Destruction","volume":"8","author":"Wehmeyer","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.orthres.2004.11.005","article-title":"Polyethylene Wear Rate and Osteolysis: Critical Threshold versus Continuous Dose-Response Relationship","volume":"23","author":"Wilkinson","year":"2005","journal-title":"J. Orthop. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1359\/jbmr.2003.18.11.1995","article-title":"Variation in the TNF Gene Promoter and Risk of Osteolysis after Total Hip Arthroplasty","volume":"18","author":"Wilkinson","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1002\/jbmr.5650100920","article-title":"The Potential Role of Fibroblasts in Periprosthetic Osteolysis: Fibroblast Response to Titanium Particles","volume":"10","author":"Yao","year":"1995","journal-title":"J. Bone Miner. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1002\/art.39183","article-title":"Brief Report: Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint","volume":"67","author":"Yeremenko","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"352","DOI":"10.3389\/fcell.2020.00352","article-title":"The Effects of Biomaterial Implant Wear Debris on Osteoblasts","volume":"8","author":"Zhang","year":"2020","journal-title":"Front. Cel. Dev. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1038\/gt.2010.64","article-title":"Cell-based Osteoprotegerin Therapy for Debris-Induced Aseptic Prosthetic Loosening on a Murine Model","volume":"17","author":"Zhang","year":"2010","journal-title":"Gene Ther."},{"key":"B49","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.tox.2012.04.002","article-title":"Inhibitory Effects of Beta-Tricalciumphosphate Wear Particles on Osteocytes via Apoptotic Response and Akt Inactivation","volume":"297","author":"Zhang","year":"2012","journal-title":"Toxicology"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.666295\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T04:31:31Z","timestamp":1624422691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.666295\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":49,"alternative-id":["10.3389\/fmolb.2021.666295"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2021.666295","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]},"article-number":"666295"}}