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Lou M. Systemic trafficking of macrophages in implant wear debris-induced periprosthetic osteolysis. SLAS Technol 2025; 31:100254. [PMID: 39914493 DOI: 10.1016/j.slast.2025.100254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/15/2025] [Accepted: 02/03/2025] [Indexed: 02/24/2025]
Abstract
Periprosthetic osteolysis (PPOL) is a significant complication post-joint replacement, often instigated by implant wear debris, leading to chronic inflammation and bone resorption. Herein, this review summarizes the immune mechanisms of PPOL, specifically, the processes where macrophages are recruited by implant wear debris, the mechanisms by which macrophages trigger inflammatory cascades, and the role of chemokines that facilitate macrophage migration, including CCL2, CCL3, CCL4, CCL5, CXCL8, CX3CL1, and XCL1. This review highlights novel findings on these processes and suggests that illustrating these mechanisms offers promising avenues for future therapeutic strategies to prevent and treat PPOL, such as the potential use of anti-inflammatory drugs.
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Affiliation(s)
- Mengyun Lou
- Department of General Practice, Shanghai Sixth People's Hospital, Shanghai 200233, China.
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Kheder W, Bouzid A, Venkatachalam T, Talaat IM, Elemam NM, Raju TK, Sheela S, Jayakumar MN, Maghazachi AA, Samsudin AR, Hamoudi R. Titanium Particles Modulate Lymphocyte and Macrophage Polarization in Peri-Implant Gingival Tissues. Int J Mol Sci 2023; 24:11644. [PMID: 37511404 PMCID: PMC10381089 DOI: 10.3390/ijms241411644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/06/2023] [Accepted: 07/09/2023] [Indexed: 07/30/2023] Open
Abstract
Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant's surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1β, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast-osteoclast activity and failure of dental implant osseointegration.
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Affiliation(s)
- Waad Kheder
- College of Dental Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Amal Bouzid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Thenmozhi Venkatachalam
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Iman M. Talaat
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Noha Mousaad Elemam
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Tom Kalathil Raju
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Soumya Sheela
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Manju Nidagodu Jayakumar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Azzam A. Maghazachi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Abdul Rani Samsudin
- College of Dental Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Rifat Hamoudi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
- ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah 27272, United Arab Emirates
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Gehrke P, Riebe O, Fischer C, Weinhold O, Dhom G, Sader R, Weigl P. Microbiological cleaning and disinfection efficacy of a three-stage ultrasonic processing protocol for CAD-CAM implant abutments. J Adv Prosthodont 2022; 14:273-284. [PMID: 36452367 PMCID: PMC9672693 DOI: 10.4047/jap.2022.14.5.273] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/19/2022] [Accepted: 09/27/2022] [Indexed: 09/22/2023] Open
Abstract
PURPOSE Computer-aided design and manufacturing (CAD-CAM) of implant abutments has been shown to result in surface contamination from site-specific milling and fabrication processes. If not removed, these contaminants can have a potentially adverse effect and may trigger inflammatory responses of the peri-implant tissues. The aim of the present study was to evaluate the bacterial disinfection and cleaning efficacy of ultrasonic reprocessing in approved disinfectants to reduce the microbial load of CAD-CAM abutments. MATERIALS AND METHODS Four different types of custom implant abutments (total N = 32) with eight specimens in each test group (type I to IV) were CAD-CAM manufactured. In two separate contamination experiments, specimens were contaminated with heparinized sheep blood alone and with heparinized sheep blood and the test bacterium Enterococcus faecium. Abutments in the test group were processed according to a three-stage ultrasonic protocol and assessed qualitatively and quantitatively by determination of residual protein. Ultrasonicated specimens contaminated with sheep blood and E. faecium were additionally eluted and the dilutions were incubated on agar plates for seven days. The determined bacterial counts were expressed as colony-forming units (CFU). RESULTS Ultrasonic reprocessing resulted in a substantial decrease in residual bacterial protein to less than 80 µg and a reduction in microbiota of more than 7 log levels of CFU for all abutment types, exceeding the effect required for disinfection. CONCLUSION A three-stage ultrasonic cleaning and disinfection protocol results in effective bacterial decontamination. The procedure is reproducible and complies with the standardized reprocessing and disinfection specifications for one- or two-piece CAD-CAM implant abutments.
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Affiliation(s)
- Peter Gehrke
- Department of Postgraduate Education, Master of Oral Implantology, Center for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe University, Frankfurt, Germany
- Private Practice for Oral Surgery and Implant Dentistry, Ludwigshafen, Germany
| | - Oliver Riebe
- HygCen Germany GmbH, Laboratory, Schwerin, Germany
| | | | - Octavio Weinhold
- Private Practice for Oral Surgery and Implant Dentistry, Ludwigshafen, Germany
| | - Günter Dhom
- Private Practice for Oral Surgery and Implant Dentistry, Ludwigshafen, Germany
| | - Robert Sader
- Department for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, Medical Center of the Goethe University Frankfurt, Germany
| | - Paul Weigl
- Department of Prosthodontics and Head of Department of Postgraduate Education, Master of Oral Implantology, Center for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe University, Frankfurt, Germany
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Lei K, Wang Y, Peng X, Yu L, Ding J. Long‐term delivery of etanercept mediated via a thermosensitive hydrogel for efficient inhibition of wear debris‐induced inflammatory osteolysis. JOURNAL OF POLYMER SCIENCE 2022. [DOI: 10.1002/pol.20220337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kewen Lei
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital and School of Stomatology Fudan University Shanghai China
| | - Yang Wang
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital and School of Stomatology Fudan University Shanghai China
| | - Xiaochun Peng
- Department of Orthopedics, The Sixth Affiliated People's Hospital Shanghai Jiao Tong University Shanghai China
| | - Lin Yu
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital and School of Stomatology Fudan University Shanghai China
| | - Jiandong Ding
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital and School of Stomatology Fudan University Shanghai China
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Tricalcium phosphate particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis in amouse osteolysis model. Int Immunopharmacol 2022; 107:108699. [PMID: 35305384 DOI: 10.1016/j.intimp.2022.108699] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/20/2022] [Accepted: 03/10/2022] [Indexed: 12/18/2022]
Abstract
Wear particles-induced inflammatory osteolysis, a major factor of aseptic loosening affects the long-term survival of orthopedic prostheses. Increasing observations have demonstrated that osteocytes, making up over 95% of all the bone cells, is involved in wear particle-induced periprosthetic osteolysis, but its mechanism remains unclear. In the present study, we embedded micro-sized tricalcium phosphate (TCP) particles (30 mg) under the periosteum around the middle suture of the mouse calvaria to establish a calvarial osteolysis model and investigated the biological effects of the particles on calvaria osteocytes in vivo. Results showed that TCP particles induced pyroptosis and activated the NLRP3 inflammasome in calvaria osteocytes, which was confirmed by obvious increases in empty lacunae, protein expressions of speck-like protein containing CARD (ASC), NOD-like receptor protein 3 (NLRP3), cleaved caspase-1 (Casp-1 p20) and cleaved gasdermin D (GSDMD-N), and resulted in elevated ratios of Casp-1 p20/Casp-1 and interleukin (IL)-1β/pro-IL-1β. Simultaneously, TCP particles enhanced serum levels of lactate dehydrogenase (LDH) and IL-1β. Furthermore, the pyroptotic effect was reversed by the Casp-1 inhibitor VX765 or the NLRP3 inhibitor MCC950. In addition, TCP particles increased the levels of intracellular reactive oxygen species (ROS) and malonaldehyde (MDA), whereas decreased the antioxidant enzyme nuclear factor E2-related factor 2 (Nrf2) level, leading to oxidative stress in calvaria osteocytes; the ROS scavenger N-acetylcysteine (NAC) attenuated these effects of pyroptotic death and the NLPR3 activation triggered by TCP particles. Collectively, our data suggested that TCP particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis, contributing to osteoclastogenesis and periprosthetic osteolysis.
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The efficacy of convenient cleaning methods applicable for customized abutments: an in vitro study. BMC Oral Health 2021; 21:78. [PMID: 33602211 PMCID: PMC7890105 DOI: 10.1186/s12903-021-01436-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/09/2021] [Indexed: 11/29/2022] Open
Abstract
Background The demand for implant dentistry, which includes customized abutments, is increasing. A lot of pollutions are generated on the customized abutment surface following milling procedure. This study evaluated the surface topography and cleanliness of customized abutments after cleaning procedures, which are simply applicable in the dental clinic. Methods Thirty computer-aided design and computer-aided manufacturing internal connection type titanium abutments were produced, milled, and randomly divided into 3 groups: steam cleaning (control group), chlorhexidine (CHX) scrubbing (test group 1), and ultrasonic cleaning with CHX solution, acetone, and ethyl alcohol (test group 2). Each group was evaluated using microscopic and microbial analysis. Results Foreign bodies were observed on the abutment surfaces in control group and test group 1, but not in test group 2. Bacteria were observed on 40% of the agar plates following steam cleaning; most of the colonies consisted of Bacillus cereus and Staphylococcus warneri. Colony growth was absent following test group 1 and 2. Conclusion For customized abutments, cleaning with steam is ineffective. CHX scrubbing effectively eliminates only bacteria. Ultrasonic cleaning with CHX solution, acetone, and ethyl alcohol successfully removes both foreign bodies and bacteria. Thus, the ultrasonic cleaning method is conveniently applicable in the dental clinic for eliminating contamination of the customized abutment surface.
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Berryman Z, Bridger L, Hussaini HM, Rich AM, Atieh M, Tawse-Smith A. Titanium particles: An emerging risk factor for peri-implant bone loss. Saudi Dent J 2020; 32:283-292. [PMID: 32874068 PMCID: PMC7452065 DOI: 10.1016/j.sdentj.2019.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/19/2019] [Accepted: 09/25/2019] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE To investigate the presence of titanium particles in peri-implant tissues in cases diagnosed with peri-implantitis, and to identify immunological reactions that these particles may elicit. METHODS Ten peri-implant tissue biopsies of patients diagnosed clinically and radiographically with peri-implantitis were obtained from the archives of Oral Pathology Centre, University of Otago. The inclusion criteria involves: bleeding on probing, ≥6 mm probing depth and ≥3 mm radiographic bone loss around the dental implant. Peri-implant tissue samples were evaluated using scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDS) to identify of sites with/without titanium particles. Antibodies against human transforming growth factor beta 1 (TGF-β1), receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin 33 (IL-33) and cluster of differentiation 68 (CD68) were used to stain the specimens. ImageJ software was used to standardise the sampling area, compare and characterise the inflammatory infiltrate in tissues with/without titanium particles. Inflammatory cytokines positivity was assessed using the immunoreactive scores (IRSs). RESULTS Light microscopy and SEM-EDS analysis identified titanium wear particles in 90% of the tissue samples, associated with a mixed chronic inflammatory infiltrate. Quantification analysis of RANKL revealed significantly higher IRS and intensity scores (p < 0.05) in areas containing titanium. High intensity, proportion and IRSs of TGF-β1 and IL-33 were observed in areas with titanium. CD68 had higher IRSs in the absence of titanium particles. CONCLUSIONS Significant overexpression of the cytokine RANKL was observed, with a trend for over-expression of IL-33 and TGF-B1 in areas with titanium. Further studies with large sample size and appropriate control group for quantification analysis is needed to confirm the role of titanium particles in initiating bone loss.
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Affiliation(s)
- Zoë Berryman
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Laura Bridger
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Haizal Mohd Hussaini
- Department of Oral Diagnostic and Surgical Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Alison M. Rich
- Department of Oral Diagnostic and Surgical Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Momen Atieh
- Mohammed Bin Rashid University of Medicine and Health Sciences, Hamdan Bin Mohammed College of Dental Medicine, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Andrew Tawse-Smith
- Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Xie X, Zhang Q, Zhang P, Zhou H, Zhang R, Wang X, Li Y. Particulate poly(methyl methacrylate) could stimulate proinflammatory CD4 T cell responses in a monocyte-dependent manner, and directly mediate cell death. Hum Immunol 2019; 80:1012-1019. [PMID: 31575437 DOI: 10.1016/j.humimm.2019.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/07/2019] [Accepted: 09/18/2019] [Indexed: 11/28/2022]
Abstract
Poly(methyl methacrylate) (PMMA) is a synthetic polymer that has been widely used in various medical implants. Traditionally considered a biologically inert material, it is now understood that PMMA may have proinflammatory properties. Here, we present a proof-of-concept study of the effect of PMMA on CD4 T cells. Using particulate PMMA, a material that resembled wear debris in orthopedic implants, to stimulate whole peripheral blood mononuclear cells, we found that the expression of IFNgamma, IL-4, IL-17, and TGFbeta could all be upregulated in CD4 T cells in a manner that was dependent on the dose of particulate PMMA. Furthermore, compared to direct anti-CD3/CD28 stimulation, PMMA preferentially stimulated the expression of IFNgamma and IL-17 but not the expression of IL-4 or TGFbeta. Interestingly, the presence of autologous monocytes was required, since PMMA had no stimulatory effect on isolated CD4 T cells. We further demonstrated that direct monocyte-CD4 T cell contact was required, and the costimulatory molecules CD80 and CD86 were involved for the optimal stimulation of CD4 T cells. PMMA also directly mediated the death of CD4 T cells in a manner that was dependent on dose but independent of the presence of monocytes. Overall, our study revealed that PMMA could induce CD4 T cell death, and also could result in CD4 T cell activation with a preference toward proinflammatory responses in a monocyte-dependent manner.
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Affiliation(s)
- Xiang Xie
- Department of Plastic Surgery, Peking University Third Hospital, Beijing, China
| | - Qingyi Zhang
- Chongqing Maen Medical Cosmetology Hospital, Chongqing, China; Jining Beiyishengxin Medical Cosmetology Institute, Jining, Shandong, China
| | - Ping Zhang
- Jining Women and Children Hospital, Jining, Shandong, China
| | - Huan Zhou
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, China
| | - Ran Zhang
- Department of Spine Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xudong Wang
- Operating Room, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yanming Li
- Department of Orthopedics, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
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Yang S, Zhang K, Jiang J, James B, Yang SY. Particulate and ion forms of cobalt-chromium challenged preosteoblasts promote osteoclastogenesis and osteolysis in a murine model of prosthesis failure. J Biomed Mater Res A 2018; 107:187-194. [PMID: 30358096 DOI: 10.1002/jbm.a.36553] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/13/2018] [Accepted: 09/17/2018] [Indexed: 12/13/2022]
Abstract
This study investigated the interactive behavior of the particulate and ion forms of cobalt-chromium (Co-Cr) alloy challenged preosteoblasts during the process of prosthetic implant loosening. Preosteoblasts were challenged with Co-Cr particles or Co(II) ions for 72 h, followed by the proliferation and PCR assays. For in vivo test, a titanium pin was implanted into proximal tibia of SCID mice to mimic knee replacement. Co-Cr particles or Co(II) ion challenged preosteoblasts (5 × 105 ) were intra-articularly injected into the implanted knee. The animals were sacrificed 5 weeks post-op, and the prosthetic knees were harvested for biomechanical pin-pullout testing, histological evaluations, and microCT assessment. In vitro study suggested that Co-Cr particles and Co(II) ions significantly suppressed the proliferation of preosteoblasts in a dose-dependent manner. RT-PCR data on the challenged cells indicated overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) and inhibited osteoprotegerin (OPG) gene expression. Introduction of the differently challenged preosteoblasts to the pin-implant mouse model resulted in reduced implant interfacial shear strength, thicker peri-implant soft-tissue formation, more TRAP+ cells, lower bone mineral density, and bone volume fraction. In conclusion, both Co-Cr particles and Co(II) ions interfered with the growth, maturation, and functions of preosteoblasts, and provides evidence that the metal ions as well play an important role in effecting preosteoblasts in the pathogenesis of aseptic loosening. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 187-194, 2019.
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Affiliation(s)
- Shuye Yang
- Department of Orthopaedic Surgery, The University of Kansas School of Medicine-Wichita, Wichita, Kansas
- Department of Orthopedic Surgery, Affiliated Hospital to Binzhou Medical College, Binzhou, 256603, China
| | - Kai Zhang
- Department of Orthopedic Surgery, Affiliated Hospital to Binzhou Medical College, Binzhou, 256603, China
| | - Jianhao Jiang
- Department of Orthopedic Surgery, Affiliated Hospital to Binzhou Medical College, Binzhou, 256603, China
| | - Bonface James
- Department of Biological Sciences, Wichita State University, Wichita, Kansas, 67260
| | - Shang-You Yang
- Department of Orthopaedic Surgery, The University of Kansas School of Medicine-Wichita, Wichita, Kansas
- Department of Biological Sciences, Wichita State University, Wichita, Kansas, 67260
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Chalmers PN, Walton D, Sporer SM, Levine BR. Evaluation of the Role for Synovial Aspiration in the Diagnosis of Aseptic Loosening After Total Knee Arthroplasty. J Bone Joint Surg Am 2015; 97:1597-603. [PMID: 26446968 DOI: 10.2106/jbjs.n.01249] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Aseptic prosthetic loosening is known to be an inflammatory, cellular process. We hypothesized that the synovial cell count would significantly differ among normal controls, patients with aseptic loosening, and patients with other etiologies of aseptic failure after total knee arthroplasty and thus that the cell count would be useful in the diagnosis of aseptic loosening. METHODS Over a six-year time period, all patients undergoing revision total knee arthroplasties at our institution underwent prospective intraoperative aspiration by the two senior authors. Each patient was assigned to a failure category on the basis of a priori criteria: aseptic loosening, periprosthetic infection, component wear, periprosthetic fracture, component malposition, instability, stiffness, and extensor mechanism failure. Simultaneously, patients with well-functioning total knee replacements underwent aspiration as normal controls. Aspirate characteristics were then compared between groups. Receiver-operating characteristic curves were created to determine optimal white blood-cell cutoffs when periprosthetic infection was compared with each individual failure category. RESULTS Thirty normal control patients and 433 patients who underwent revision total knee arthroplasties were included in this study. The synovial white blood-cell count in the normal control group was 558 ± 522 cells/μL, which did not significantly differ (p = 0.091) from that taken from patients with aseptic loosening (947 ± 1027 cells/μL). However, normal controls had significantly higher white blood-cell counts than subjects with stiffness (367 ± 392 cells/μL; p = 0.002) and significantly lower white blood-cell counts than subjects with periprosthetic fractures (1687 ± 1613 cells/μL; p = 0.002). Subjects with aseptic loosening had significantly higher white blood-cell counts than subjects with component malpositioning (p = 0.002) or stiffness (p = 0.001). When individual aseptic failure categories were compared with periprosthetic infection, the optimal white blood-cell cutoff varied widely, including 2104 cells/μL for component malposition and 4697 cells/μL for periprosthetic fracture, and the optimal differential segmented cell count percentages varied from 47% to 83%. CONCLUSIONS Although synovial fluid aspirates in patients with aseptic loosening and those with normal total knee arthroplasties did not differ, synovial fluid aspirate characteristics differed among categories of aseptic failure. As a result, the optimal diagnosis of periprosthetic infection on the basis of synovial aspiration results may need to utilize different cutoff values depending on the alternative mode of failure being considered. Large prospective studies will be necessary to validate these threshold values.
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Affiliation(s)
- Peter N Chalmers
- Department of Orthopaedic Surgery, Rush University Medical Center, 1611 West Harrison Street, Suite 300, Chicago, IL 60612. E-mail address for P.N. Chalmers:
| | - David Walton
- Department of Orthopaedic Surgery, Rush University Medical Center, 1611 West Harrison Street, Suite 300, Chicago, IL 60612. E-mail address for P.N. Chalmers:
| | - Scott M Sporer
- Department of Orthopaedic Surgery, Rush University Medical Center, 1611 West Harrison Street, Suite 300, Chicago, IL 60612. E-mail address for P.N. Chalmers:
| | - Brett R Levine
- Department of Orthopaedic Surgery, Rush University Medical Center, 1611 West Harrison Street, Suite 300, Chicago, IL 60612. E-mail address for P.N. Chalmers:
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Yang S, Zhang K, Li F, Jiang J, Jia T, Yang SY. Biological responses of preosteoblasts to particulate and ion forms of Co-Cr alloy. J Biomed Mater Res A 2015; 103:3564-71. [PMID: 25966675 DOI: 10.1002/jbm.a.35501] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 05/02/2015] [Accepted: 05/07/2015] [Indexed: 11/12/2022]
Abstract
This study compared the particulate and ion forms of a cobalt-chrome (Co-Cr) alloy on the differentiation/activation of preosteoblasts. Mouse preosteoblasts (MC3T3-E1) were cultured in an osteoblast-induction medium in the presence of particulate and ion forms of a Co-Cr alloy, followed by cell proliferation and cytotoxicity evaluations. The maturation and function of osteoblasts were assessed by alkaline phosphatase (ALP) assay and related gene expressions. Both particulate and ion forms of the metals significantly reduced the proliferation of MC3T3-E1 cells in a dose-dependent manner. Similarly, cells challenged with high concentrations of particles and ions exhibited a marked cytotoxic effect and diminished expression of ALP. Real-time (RT) polymerase chain reaction (PCR) data have suggested that cells with Co-Cr particles dramatically promoted over-expression of monocyte chemo-attractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), whereas Co(2+) ions treatment predominately up-regulated expressions of receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and down-regulated expression of osteoprotegerin (OPG) and Osterix (Osx). Overall, this study provides evidence that both Co-Cr alloy particles and metal ions interfered with the MC3T3-E1 cells for their growth, maturation, and functions. Further, Co-Cr particles exhibited stronger effects on inflammatory mediators, while metal ions showed more influence on inhibition of osteoblast differentiation and promotion of osteoclastogenesis.
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Affiliation(s)
- Shuye Yang
- Department of Orthopaedic Surgery, Jinan Central Hospital, Shandong University, Jinan, 250013, China.,Department of Biological Sciences, Wichita State University, Wichita, Kansas, 67214.,Department of Orthopaedics, Affiliated Hospital to Binzhou Medical College, Binzhou, China
| | - Kai Zhang
- Department of Orthopaedics, Affiliated Hospital to Binzhou Medical College, Binzhou, China
| | - Fangfang Li
- Department of Gynaecology and Obstetrics, Affiliated Hospital to Binzhou Medical College, Binzhou, China
| | - Jianhao Jiang
- Department of Orthopaedic Surgery, Jinan Central Hospital, Shandong University, Jinan, 250013, China
| | - Tanghong Jia
- Department of Orthopaedic Surgery, Jinan Central Hospital, Shandong University, Jinan, 250013, China
| | - Shang-You Yang
- Department of Orthopaedic Surgery, Jinan Central Hospital, Shandong University, Jinan, 250013, China.,Department of Biological Sciences, Wichita State University, Wichita, Kansas, 67214
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12
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Bitar D, Parvizi J. Biological response to prosthetic debris. World J Orthop 2015; 6:172-189. [PMID: 25793158 PMCID: PMC4363800 DOI: 10.5312/wjo.v6.i2.172] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Revised: 05/28/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic host response to generated wear débris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics (size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression.
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Zhang K, Yang SY, Yang S, Bai L, Li P, Liu D, Schurman JR, Wooley PH. Different influence of Ti, PMMA, UHMWPE, and Co-Cr particles on peripheral blood monocytes during periprosthetic inflammation. J Biomed Mater Res A 2014; 103:358-64. [PMID: 24659563 DOI: 10.1002/jbm.a.35176] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/19/2014] [Accepted: 03/21/2014] [Indexed: 12/28/2022]
Affiliation(s)
- Kai Zhang
- Department of Orthopaedics; Affiliated Hospital to Binzhou Medical College; Binzhou China
| | - Shang-You Yang
- Department of Biological Sciences; Wichita State University; Wichita Kansas 67214
- Orthopaedic Research Institute; Via Christi Hospital St. Francis; Wichita Kansas 67214
| | - Shuye Yang
- Department of Orthopaedics; Affiliated Hospital to Binzhou Medical College; Binzhou China
- Department of Biological Sciences; Wichita State University; Wichita Kansas 67214
| | - Ling Bai
- Orthopaedic Research Institute; Via Christi Hospital St. Francis; Wichita Kansas 67214
| | - Peng Li
- Department of Orthopaedics; Affiliated Hospital to Binzhou Medical College; Binzhou China
| | - Dong Liu
- Department of Orthopaedics; Affiliated Hospital to Binzhou Medical College; Binzhou China
| | | | - Paul H. Wooley
- Department of Biological Sciences; Wichita State University; Wichita Kansas 67214
- Orthopaedic Research Institute; Via Christi Hospital St. Francis; Wichita Kansas 67214
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Correlation of aspiration results with aseptic loosening in total hip arthroplasty. J Arthroplasty 2013; 28:1671-6. [PMID: 23806183 DOI: 10.1016/j.arth.2013.05.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 05/20/2013] [Indexed: 02/01/2023] Open
Abstract
In the evaluation of patients with a persistently painful total hip arthroplasty establishing an accurate diagnosis is paramount in the selection of a successful treatment regimen. It is unknown whether synovial analysis might differentiate aseptic loosening from other causes of failure. A physiological basis exists to suggest that aseptic loosening might be a process of non-segmented leukocytes. The objective of this study was to determine if the synovial fluid differential cell count might aid in the diagnosis of aseptic loosening. A retrospective chart review of all patients who had undergone revision hip arthroplasty with pre-operative or intra-operative aspiration results was performed. Aseptic loosening was defined as gross intraoperative movement in the absence of infection. From these results Relative-Operating Characteristic (ROC) curves were created, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. A diagnosis of aseptic loosening was established in 76 of the 253 hips. The ROC curves indicated that lymphocyte count does have utility in the diagnosis of aseptic loosening. If an aspirate has a combination of fewer than 2500 WBCs (sensitivity 93%, specificity 42%, NPV 94%, accuracy 57%) or more than 10% lymphocytes (sensitivity 86%, specificity 42%, NPV 87%, accuracy 55%) then the sensitivity for aseptic loosening is 96%, the specificity is 33%, the NPV is 95% and the accuracy is 52%. In patients with painful total hip arthroplasties in whom infection has been excluded, aspiration data can be a useful adjunct in the diagnosis of aseptic loosening. In aspirates with neither a WBC cell count of less than 2500 nor a lymphocyte cell count of greater than 10% aseptic loosening can be effectively "ruled out" as fewer than 5% of these patients will have aseptic loosening. While non-specific, aspirate differential can be useful to "rule-out" aseptic loosening with a sensitivity and negative predictive value well exceeding that of standard radiographs.
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Nich C, Takakubo Y, Pajarinen J, Ainola M, Salem A, Sillat T, Rao AJ, Raska M, Tamaki Y, Takagi M, Konttinen YT, Goodman SB, Gallo J. Macrophages-Key cells in the response to wear debris from joint replacements. J Biomed Mater Res A 2013; 101:3033-45. [PMID: 23568608 PMCID: PMC3775910 DOI: 10.1002/jbm.a.34599] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 11/16/2012] [Accepted: 01/12/2013] [Indexed: 12/14/2022]
Abstract
The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented.
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Affiliation(s)
- Christophe Nich
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California; Laboratoire de Biomécanique et Biomatériaux Ostéo-Articulaires-UMR CNRS 7052, Faculté de Médecine-Université Paris 7, Paris, France; Department of Orthopaedic Surgery, European Teaching Hospital, Assistance Publique-Hôpitaux de Paris-Université Paris 5, Paris, France
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Jiang Y, Jia T, Gong W, Wooley PH, Yang SY. Titanium particle-challenged osteoblasts promote osteoclastogenesis and osteolysis in a murine model of periprosthestic osteolysis. Acta Biomater 2013; 9:7564-72. [PMID: 23518478 DOI: 10.1016/j.actbio.2013.03.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 02/28/2013] [Accepted: 03/04/2013] [Indexed: 02/07/2023]
Abstract
The current study investigates the interactive behavior of titanium alloy particle-challenged osteoblastic bone marrow stromal cells (BMSCs) and macrophage lineage cells in a murine knee-prosthesis failure model. BMSCs were isolated from male BALB/c mice femurs and induced in osteogenic medium. At 24h after isolation, BMSCs in complete induction medium were challenged with 1, 3 or 5mgml(-1) titanium particles for 7days. Culture media were collected at 2, 4 and 6days and cells were harvested at 7days for alkaline phosphatase (ALP) assay/stains. Cell proliferation in the presence of Ti particles was periodically evaluated by MTT assay. Mice implanted with titanium-pin tibial implants were given an intra-articular injection of 50μl medium containing 5×10(5) Ti particles-challenged bone-marrow-derived osteoblastic cells, followed by a repeat injection at 2weeks post-operation. Control mice with titanium-pin implants received a naïve osteoblastic cell transfusion. After sacrifice at 4weeks, the implanted knee joint of each group was collected for biomechanical pin-pullout testing, histological evaluation and reverse transcriptase polymerase chain reaction analysis of mRNA extracted from the joint tissues. Ti particles significantly stimulated the proliferation of BMSC-derived osteoblastic cells at both high and low particle concentrations (p<0.05), with no marked differences between the particle doses. ALP expression was diminished following Ti particle interactions, especially in the high-dose particle group (p<0.05). In addition, the culture media collected from short-term challenged (48h) osteoblasts significantly increased the numbers of TRAP+ cells when added to mouse peripheral blood monocytes cultures, in comparison with the monocytes cells receiving naïve osteoblasts media (p<0.05). Intra-articular introduction of the osteoblastic cells to the mouse pin-implant failure model resulted in reduced implant interfacial shear strength and thicker peri-implant soft-tissue formation, suggesting that titanium particles-challenged osteoblasts contributed to periprosthetic osteolysis. Comparison of the gene expression profiles among the peri-implant tissue samples following osteoblast injection did not find significant difference in RunX2 or Osterix/Sp7 between the groups. However, MMP-2, IL-1, TNF-α, RANKL, and TRAP gene expressions were elevated in the challenged-osteoblast group (p<0.05). In conclusion, titanium alloy particles were shown to interfere with the growth, maturation, and functions of the bone marrow osteoblast progenitor cells. Particle-challenged osteoblasts appear to express mediators that regulate osteoclastogenesis and peri-prosthetic osteolysis.
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Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis. J Orthop Sci 2013; 18:478-85. [PMID: 23553541 DOI: 10.1007/s00776-013-0362-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 01/25/2013] [Indexed: 02/09/2023]
Abstract
BACKGROUND Osteoporosis is a common pathological condition that influences 20 % of women over 50 years of age. This condition decreases bone strength and increases the risk of bone fracture. Naringin is a major flavonoid found in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae). Studies have shown that naringin possesses many pharmacological effects. The current study evaluated the influence of naringin on osteoblastic cell differentiation and proliferation, and assessed its therapeutic effects on a rat osteoporosis model. METHOD The proliferation, differentiation, and function of rat bone marrow stromal cells (BMSCs) were determined following treatment with various concentrations of naringin. Ovariectomy (OVX)-induced osteoporotic rats were orally administered naringin daily at low, medium, and high dosages, while a control group received PBS for 2 months. Femoral X-ray images and microCT scans were used for bone mineral density (BMD) and BV/TV (bone volume/total volume) analyses, and histological assessments of left tibiae were employed to check for changes in trabecular thickness (Tb.Th) and trabecular space (Tb.Sp) in the groups. RESULTS Naringin was effective at enhancing the proliferation and osteogenic differentiation of BMSCs, and a concentration of 10 μg/ml prompted the highest levels of osteocalcin expression among the in vitro study groups. There appeared to be a delayed response pattern of BMSCs to the naringin treatment. Naringin also effectively reversed OVX-induced bone loss via increasing BMD, bone volume, and trabecular thickness. The medium dose (300 mg/kg) appeared to be the optimal dosage for delivering satisfactory therapeutic effects. CONCLUSION Naringin promotes the proliferation and differentiation of BMSCs, and increases osteocalcin expression. Naringin also effectively reverses ovariectomy-induced osteoporosis in rats. The study suggests that naringin administration may represent an effective treatment for osteoporosis.
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Jiang Y, Jia T, Gong W, Wooley PH, Yang SY. Effects of Ti, PMMA, UHMWPE, and Co-Cr wear particles on differentiation and functions of bone marrow stromal cells. J Biomed Mater Res A 2013; 101:2817-25. [PMID: 24039045 DOI: 10.1002/jbm.a.34595] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/07/2012] [Accepted: 01/09/2013] [Indexed: 11/10/2022]
Abstract
This study investigates the roles of orthopedic biomaterial particles [Ti-alloy, poly(methyl methacrylate) (PMMA), ultrahigh-molecular-weight polyethylene (UHMWPE), Co-Cr alloy] on the differentiation and functions of bone marrow stromal cells (BMSCs). Cells were isolated from femurs of BALB/c mice and cultured in complete osteoblast-induction medium in presence of micron-sized biomaterial particles at various doses. 3-(4,5)-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase assay were performed for cell proliferation and cytotoxicity. Differentiation and function of osteoblasts were evaluated by alkaline phosphatase (ALP), osteocalcin, RANKL, OSX, and Runx2 expressions. Murine interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α in culture media were determined by enzyme-linked immunosorbent assay. Challenge with low doses of Ti, UHMWPE, or Co-Cr particles markedly promoted the bone marrow cell proliferation while high dose of Co-Cr significantly inhibited cell growth (p < 0.05). Cells challenged with low dose of PMMA or UHMWPE particles (0.63 mg/mL) exhibited strong ALP activity, whereas Ti and Co-Cr groups showed minimal effects (p < 0.05). UHMWPE and Ti particles also promoted higher expression of proinflammatory cytokines. Real-time polymerase chain reaction data suggested that cells treated with low dose (0.5 mg/mL) particles resulted in distinctly diminished RANKL expression compared to those exposed to high concentrated (3 mg/mL) particles. In conclusion, various types of wear debris particles behaved differently in the differentiation, maturation, and functions of osteogenic cells; and the particulate debris-interacted BMSCs may play an important role in the pathogenesis and process of the debris-associated aseptic prosthetic loosening.
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Affiliation(s)
- Yunpeng Jiang
- Orthopaedic Research Institute, Via Christi Wichita Hospitals, Wichita, Kansas; Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China; Department of Biological Sciences, Wichita State University, Wichita, Kansas
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Yang Z, Huang B, Zhang Z, Kang Y, Fu M, Liao W. Effects of IL-1 receptor-associated kinase-4 gene silencing on human osteoblast-like cells. Connect Tissue Res 2012; 53:498-507. [PMID: 22606974 DOI: 10.3109/03008207.2012.694927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The aim of this study is to identify the effects of interleukin-1 receptor-associated kinase-4 (IRAK-4) gene silencing on human osteoblast-like cells. The siRNA sequences of the target gene, IRAK-4, were constructed and transferred into MG63 cells (control group = MG63 cells; SC group = MG63 cells transfected with scrambled IRAK-4 siRNA; KD group = MG63 cells transfected with 75 nM IRAK-4 siRNA). The morphological changes, cell growth, cell-cycle progression, apoptosis, and the expression of various cytokines and proteins were compared. Compared with the control and SC groups, IRAK-4 gene silencing in MG63 cells caused morphological changes, inhibited growth, altered the cell-cycle distribution, increased apoptosis (p < 0.05), decreased bone alkaline phosphatase and osteocalcin levels (p < 0.05), and decreased protein expression of Bcl-2/Bax and Bcl-2, p-JNK1/2, p-ERK1/2, and p-p38MAPK (p < 0.05). The results indicated that IRAK-4 gene silencing in MG63 cells inhibited cell proliferation and function and increase apoptosis, which may be related to the decreased Bcl-2/Bax ratio and inhibition of the protein expression of various components of the mitogen-activated protein kinase pathways. The results of this study may help improve the understanding of the relationship between IRAK-4 and osteoblast-like cells and the interactions between various cytokines in the periprosthetic inflammatory environment.
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Affiliation(s)
- Zibo Yang
- Department of Orthopedic and Joint Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
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Canullo L, Micarelli C, Iannello G. Microscopical and chemical surface characterization of the gingival portion and connection of an internal hexagon abutment before and after different technical stages of preparation. Clin Oral Implants Res 2012; 24:606-11. [DOI: 10.1111/j.1600-0501.2012.02499.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2012] [Indexed: 12/14/2022]
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