Therapeutic effects of MSCs, genetically modified MSCs, and NFĸB‐inhibitor on chronic inflammatory osteolysis in aged mice

The number of total joint replacements is increasing, especially in elderly patients, and so too are implant‐related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF‐ĸB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically‐modified NF‐ĸB sensing interleukin‐4 over‐secreting MSCs (IL4‐MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15−17 months old) for 6 weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast‐like cells, increased alkaline phosphatase (ALP)‐positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4‐MSCs significantly decreased osteoclast‐like cells and increased the M2/M1 ratio, with a greater trend for IL4‐MSCs than MSCs. MSCs significantly increased ALP‐positive area and BMD values compared with the control. The IL4‐MSCs demonstrated higher values for both ALP‐positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4‐MSCs on chronic inflammatory osteolysis in aged mice. The two MSC‐based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4‐MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle‐associated inflammatory osteolysis after arthroplasty in the elderly.

[1]  S. Goodman,et al.  Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice , 2021, Frontiers in Cell and Developmental Biology.

[2]  J. Jacobs,et al.  Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner , 2021, PloS one.

[3]  S. Goodman,et al.  Suppression of NF-κB-induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model. , 2021, Journal of biomedical materials research. Part A.

[4]  A. Movila,et al.  Glycyrrhizin mitigates inflammatory bone loss and promotes expression of senescence-protective sirtuins in an aging mouse model of periprosthetic osteolysis , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  S. Goodman,et al.  Different Effects of Intramedullary Injection of Mesenchymal Stem Cells During the Acute vs. Chronic Inflammatory Phase on Bone Healing in the Murine Continuous Polyethylene Particle Infusion Model , 2021, Frontiers in Cell and Developmental Biology.

[6]  Zhenzhen Wang,et al.  Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches , 2020, Bioactive materials.

[7]  S. Goodman,et al.  PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration , 2020, Stem Cell Research & Therapy.

[8]  Roel P. H. De Maeyer,et al.  The impact of ageing on monocytes and macrophages. , 2020, Immunology letters.

[9]  G. Courties,et al.  New Insights into Macrophage Heterogeneity in Rheumatoid Arthritis. , 2020, Joint bone spine.

[10]  M. Tognon,et al.  Adult Stem Cells for Bone Regeneration and Repair , 2019, Front. Cell Dev. Biol..

[11]  R. Wong,et al.  Vibration treatment modulates macrophage polarisation and enhances early inflammatory response in oestrogen-deficient osteoporotic-fracture healing. , 2019, European cells & materials.

[12]  S. Goodman,et al.  Inflammation and Bone Repair: From Particle Disease to Tissue Regeneration , 2019, Front. Bioeng. Biotechnol..

[13]  S. Goodman,et al.  Optimization and characterization of calcium phosphate transfection in mesenchymal stem cells. , 2019, Tissue engineering. Part C, Methods.

[14]  Fan Yang,et al.  Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages. , 2019, Tissue engineering. Part A.

[15]  M. Glogauer,et al.  An Overview of the Derivation and Function of Multinucleated Giant Cells and Their Role in Pathologic Processes. , 2019, The American journal of pathology.

[16]  Yusuke Kohno,et al.  Mesenchymal stem cell-macrophage crosstalk and bone healing. , 2019, Biomaterials.

[17]  Dan-dan Li,et al.  Improved therapeutic potential of MSCs by genetic modification , 2018, Gene Therapy.

[18]  S. Goodman,et al.  NFκB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles. , 2018, Journal of biomedical materials research. Part A.

[19]  S. Goodman,et al.  Transplanted interleukin-4--secreting mesenchymal stromal cells show extended survival and increased bone mineral density in the murine femur. , 2018, Cytotherapy.

[20]  R. Satija,et al.  Single-cell RNA sequencing to explore immune cell heterogeneity , 2017, Nature Reviews Immunology.

[21]  S. Goodman,et al.  Orthopaedic wear particle-induced bone loss and exogenous macrophage infiltration is mitigated by local infusion of NF-κB decoy oligodeoxynucleotide. , 2017, Journal of biomedical materials research. Part A.

[22]  S. Goodman,et al.  * Murine Model of Progressive Orthopedic Wear Particle-Induced Chronic Inflammation and Osteolysis. , 2017, Tissue engineering. Part C, Methods.

[23]  S. Goodman,et al.  Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an "on-demand" drug delivery system to modulate inflammation. , 2017, Cytotherapy.

[24]  Fan Yang,et al.  Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model. , 2017, Biomaterials.

[25]  Peter Bankhead,et al.  QuPath: Open source software for digital pathology image analysis , 2017, Scientific Reports.

[26]  R. Miron,et al.  Giant cells around bone biomaterials: Osteoclasts or multi-nucleated giant cells? , 2016, Acta biomaterialia.

[27]  S. Goodman,et al.  NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model. , 2016, Acta biomaterialia.

[28]  S. Goodman,et al.  Emperor's new clothes: Is particle disease really infected particle disease? , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[29]  Fan Yang,et al.  The effect of local IL-4 delivery or CCL2 blockade on implant fixation and bone structural properties in a mouse model of wear particle induced osteolysis. , 2016, Journal of biomedical materials research. Part A.

[30]  S. Goodman,et al.  Aging Affects Bone Marrow Macrophage Polarization: Relevance to Bone Healing , 2016, Regenerative Engineering and Translational Medicine.

[31]  E. Schwarz,et al.  Antioxidant impregnated ultra‐high molecular weight polyethylene wear debris particles display increased bone remodeling and a superior osteogenic:osteolytic profile vs. conventional UHMWPE particles in a murine calvaria model , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[32]  O. Muratoglu,et al.  Biological reaction to polyethylene particles in a murine calvarial model is highly influenced by age , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[33]  T. Einhorn,et al.  Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFα signaling , 2016, Scientific Reports.

[34]  Dong-Hyun Kim,et al.  Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice , 2016, BMC Microbiology.

[35]  K. Moore,et al.  Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis , 2015, Annals of the rheumatic diseases.

[36]  D. Naudie,et al.  Highly cross-linked polyethylene decreases the rate of revision of total hip arthroplasty compared with conventional polyethylene at 13 years' follow-up. , 2016, The bone & joint journal.

[37]  S. Goodman,et al.  NF-κB decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model. , 2015, Journal of biomedical materials research. Part A.

[38]  Y. Konttinen,et al.  Establishment of Green Fluorescent Protein and Firefly Luciferase Expressing Mouse Primary Macrophages for In Vivo Bioluminescence Imaging , 2015, PloS one.

[39]  P. Cram,et al.  The Effect of Advancing Age on Total Joint Replacement Outcomes , 2015, Geriatric orthopaedic surgery & rehabilitation.

[40]  S. Goodman,et al.  NF-κB decoy oligodeoxynucleotide enhanced osteogenesis in mesenchymal stem cells exposed to polyethylene particle. , 2015, Tissue engineering. Part A.

[41]  B. Cronstein,et al.  Brief Report: Methotrexate Prevents Wear Particle–Induced Inflammatory Osteolysis in Mice Via Activation of Adenosine A2A Receptor , 2015, Arthritis & rheumatology.

[42]  Fan Yang,et al.  Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-κB decoy oligodeoxynucleotide: a preliminary report. , 2014, Acta biomaterialia.

[43]  J. Glowacki,et al.  Effect of Age on Regulation of Human Osteoclast Differentiation , 2014, Journal of cellular biochemistry.

[44]  S. Goodman,et al.  11 – Failure mechanisms in joint replacement* , 2014 .

[45]  S. Goodman,et al.  Macrophage polarization in response to wear particles in vitro , 2013, Cellular and Molecular Immunology.

[46]  A. Leithner,et al.  Revision surgery after total joint arthroplasty: a complication-based analysis using worldwide arthroplasty registers. , 2013, The Journal of arthroplasty.

[47]  S. Goodman,et al.  Direct subcutaneous injection of polyethylene particles over the murine calvaria results in dramatic osteolysis , 2013, International Orthopaedics.

[48]  A. Schilling,et al.  RANKL-associated suppression of particle-induced osteolysis in an aged model of Calcitonin and α-CGRP deficiency. , 2013, Biomaterials.

[49]  Y. Abu-Amer.  NF-κB signaling and bone resorption , 2012, Osteoporosis International.

[50]  S. Goodman,et al.  The basic science of periprosthetic osteolysis. , 2013, Instructional course lectures.

[51]  C. Cooper,et al.  The lifetime risk of total hip and knee arthroplasty: results from the UK general practice research database. , 2012, Osteoarthritis and cartilage.

[52]  S. Gambhir,et al.  MC3T3-E1 osteoprogenitor cells systemically migrate to a bone defect and enhance bone healing. , 2012, Tissue engineering. Part A.

[53]  P. Marie,et al.  Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions , 2011, Aging cell.

[54]  S. Goodman,et al.  Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis , 2011, Clinical orthopaedics and related research.

[55]  Victor M. Goldberg,et al.  Bacterial Pathogen-associated Molecular Patterns Stimulate Biological Activity of Orthopaedic Wear Particles by Activating Cognate Toll-like Receptors* , 2010, The Journal of Biological Chemistry.

[56]  Xiaodong Chen,et al.  Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair , 2010, Cell Research.

[57]  R. Morishita,et al.  New treatment of periodontal diseases by using NF-kappaB decoy oligodeoxynucleotides via prevention of bone resorption and promotion of wound healing. , 2009, Antioxidants & redox signaling.

[58]  Jiake Xu,et al.  NF-kappaB modulators in osteolytic bone diseases. , 2009, Cytokine & growth factor reviews.

[59]  S. Goodman,et al.  In vivo murine model of continuous intramedullary infusion of particles--a preliminary study. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[60]  D. Lindsey,et al.  An in vivo murine model of continuous intramedullary infusion of polyethylene particles. , 2008, Biomaterials.

[61]  Anna Kowalczyk,et al.  Osteoarthritis of the knee. , 2008, American family physician.

[62]  S. Goodman.  Wear particles, periprosthetic osteolysis and the immune system. , 2007, Biomaterials.

[63]  S. Bandinelli,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC only. TRIALS The , 2004 .

[64]  J. Clohisy,et al.  NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[65]  B. Aggarwal,et al.  Nuclear factor-kappaB: its role in health and disease. , 2004, Journal of molecular medicine.

[66]  W. Maloney,et al.  Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titanium-alloy particulate debris in vitro. , 1999, The Journal of bone and joint surgery. American volume.

[67]  G. Paolisso,et al.  Advancing age and insulin resistance: role of plasma tumor necrosis factor-alpha. , 1998, The American journal of physiology.

[68]  H. Bertram,et al.  Osteolysis in alloarthroplasty of the hip. The role of ultra-high molecular weight polyethylene wear particles. , 1990, Clinical orthopaedics and related research.