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Wear particle‐associated bone loss (periprosthetic osteolysis) constrains the longevity of total joint arthroplasty (TJA). Wear particles induce a prolonged upregulation of nuclear factor kappa B (NF‐κB) signaling in macrophages and osteoclasts. Synthetic double‐stranded oligodeoxynucleotides (ODNs) can prevent the binding of NF‐κB to the promoter regions of targeted genes and inhibit genetic activation. We tested the hypothesis that polyethylene‐particle induced chronic inflammatory bone loss could be suppressed by local delivery of NF‐κB decoy ODNs in murine in vivo model. Polyethylene particles were continuously infused into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation, and micro‐computational tomography and immunohistochemical analysis were performed. Particle‐induced chronic inflammation resulted in lower BMD values, an increase in osteoclastogenesis and nuclear translocation of p65, a prolonged M1 pro‐inflammatory macrophage phenotype, and a decrease of M2 anti‐inflammatory macrophage phenotype. Delayed timing of local infusion of NF‐κB decoy ODN for the last 3 weeks reversed polyethylene‐particle associated chronic inflammatory bone loss and facilitated bone healing. This study demonstrated that polyethylene‐particle associated chronic inflammatory osteolysis can be effectively modulated via interference with the NF‐κB pathway; this minimally invasive intervention could potentially be an efficacious therapeutic strategy for periprosthetic osteolysis after TJA. [ABSTRACT FROM AUTHOR]

Periprosthetic osteolysis remains as a major complication of total joint replacement surgery. Modulation of macrophage polarization with interleukin‐4 (IL‐4) has emerged as an effective means to limit wear particle‐induced osteolysis. The aim of this study was to evaluate the efficacy of local IL‐4 delivery in treating preexisting particle‐induced osteolysis. To this end, recently established 8 week modification of murine continuous femoral intramedullary particle infusion model was utilized. Subcutaneous infusion pumps were used to deliver polyethylene (PE) particles into mouse distal femur for 4 weeks to induce osteolysis. IL‐4 was then added to the particle infusion for another 4 weeks. This delayed IL‐4 treatment (IL‐4 Del) was compared to IL‐4 delivered continuously (IL‐4 Cont) with PE particles from the beginning and to the infusion of particles alone for 8 weeks. Both IL‐4 treatments were highly effective in preventing and repairing preexisting particle‐induced bone loss as assessed by μCT. Immunofluorescence indicated a significant reduction in the number of F4/80 + iNOS + M1 macrophages and increase in the number of F4/80 + CD206 + M2 macrophages with both IL‐4 treatments. Reduction in the number of tartrate resistant acid phosphatase + osteoclasts and increase in the amount of alkaline phosphatase (ALP) + osteoblasts was also observed with both IL‐4 treatments likely explaining the regeneration of bone in these samples. Interesting, slightly more bone formation and ALP + osteoblasts were seen in the IL‐4 Del group than in the IL‐4 Cont group although these differences were not statistically significant. The study is a proof of principle that osteolytic lesions can be repaired via modulation of macrophage polarization. [ABSTRACT FROM AUTHOR]

Although core decompression (CD) is often performed in the early stage of osteonecrosis of the femoral head (ONFH), the procedure does not always prevent subsequent deterioration and the effects of CD are not fully clarified. The aim of this study is to evaluate the efficacy of CD for steroid‐associated ONFH in rabbits. Twelve male and 12 female New Zealand rabbits were injected intramuscularly 20 mg/kg of methylprednisolone once and were divided into the disease control and CD groups. In the disease control group, rabbits had no treatment and were euthanized at 12 weeks postinjection. In the CD group, rabbits underwent left femoral CD at 4 weeks postinjection and were euthanized 8 weeks postoperatively. The left femurs were collected to perform morphological, biomechanical, and histological analysis. Bone mineral density and bone volume fraction in the femoral head in the CD group were significantly higher than in the disease control group. However, no difference in the mechanical strength was observed between the two groups. Histological analysis showed that alkaline phosphatase and CD31 positive cells significantly increased in the males after CD treatment. The number of empty lacunae in the surrounding trabecular bone was significantly higher in the CD group. The current study indicated that CD improved the morphological properties, but did not improve the mechanical strength in the femoral head at early‐stage ONFH. These data suggest the need for additional biological, mechanical strategies, and therapeutic windows to improve the outcome of early‐stage steroid‐associated ONFH. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC)‐based therapy is a promising strategy for bone repair. Furthermore, the innate immune system, and specifically macrophages, plays a crucial role in the differentiation and activation of MSCs. The anti‐inflammatory cytokine Interleukin‐4 (IL‐4) converts pro‐inflammatory M1 macrophages into a tissue regenerative M2 phenotype, which enhances MSC differentiation and function. We developed lentivirus‐transduced IL‐4 overexpressing MSCs (IL‐4 MSCs) that continuously produce IL‐4 and polarize macrophages toward an M2 phenotype. In the current study, we investigated the potential of IL‐4 MSCs delivered using a macroporous gelatin‐based microribbon (μRB) scaffold for healing of critical‐size long bone defects in Mice. IL‐4 MSCs within μRBs enhanced M2 marker expression without inhibiting M1 marker expression in the early phase, and increased macrophage migration into the scaffold. Six weeks after establishing the bone defect, IL‐4 MSCs within μRBs enhanced bone formation and helped bridge the long bone defect. IL‐4 MSCs delivered using macroporous μRB scaffold is potentially a valuable strategy for the treatment of critical‐size long bone defects. [ABSTRACT FROM AUTHOR]

Cell therapy using bone marrow concentrate (BMC) or purified and expanded mesenchymal stem cells (MSCs) has been shown to have a promising osteogenic capacity. However, few studies have directly compared their relative osteogenic ability. The aim of this study was to compare the osteogenic ability of BMC isolated by density gradient centrifugation with bone marrow‐derived MSCs in vitro using the cells of 3‐month‐old Sprague–Dawley rats. The isolated cells were seeded onto 24‐well plates (1 × 105 cells/well) and cultured in control growth media, osteogenic media with dexamethasone, or media without dexamethasone (which simulated the in vivo tissue environment). Alkaline phosphatase activity at week 2, osteocalcin using quantitative real‐time polymerase chain reaction at week 4, and Alizarin red staining at week 4 were evaluated. In the osteogenic media with dexamethasone, BMC showed equivalent (osteocalcin) or even greater (Alizarin red staining) osteogenic ability compared to MSCs, suggesting that cross‐talk among various cells in the BMC leads to greater osteogenesis. Furthermore, in the osteogenic media without dexamethasone, BMC showed equivalent (osteocalcin) or a trend for greater (Alizarin red staining) bone formation than MSCs alone. Our results suggest that BMC has at least comparable bone regeneration potential to MSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2500–2506, 2019 [ABSTRACT FROM AUTHOR]

Total joint replacement is a highly effective treatment for patients with end‐stage arthritis. Proinflammatory macrophages (M1) mediate wear particle‐associated inflammation and bone loss. Anti‐inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)‐based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of (1) unmodified MSCs, (2) MSCs preconditioned by NFκB stimulating ligands [lipopolysaccharide (LPS) plus TNFα], and (3) genetically modified MSCs that secrete IL‐4 as a response to NFκB activation (NFκB‐IL4) was compared in a macrophage/MSC co‐culture system. Sterile or LPS‐contaminated ultra‐high molecular weight polyethylene particles were used to induce the proinflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFα, IL1β, and iNOS), while NFκB‐IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg 1 and CD206 high). The IL4 secretion by NFκB‐IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naïve MSCs was negligible when compared with NFκB‐IL4 MSC. Our findings indicated that NFκB‐IL4 MSCs have the "on‐demand" immunomodulatory ability to mitigate wear particle‐associated inflammation with minimal adverse effects. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2744–2752, 2018. [ABSTRACT FROM AUTHOR]

Excessive production of wear particles from total joint replacements induces chronic inflammation, macrophage infiltration, and consequent bone loss (periprosthetic osteolysis). This inflammation and bone remodeling are critically regulated by the transcription factor NF-κB. We previously demonstrated that inhibition of NF-κB signaling by using the decoy oligodeoxynucleotide (ODN) mitigates polyethylene wear particle-induced bone loss using in vitro and in vivo models. However, the mechanisms of NF-κB decoy ODN action, and in particular its impact on systemic macrophage recruitment, remain unknown. In the current study, this systemic macrophage infiltration was examined in our established murine femoral continuous particle infusion model. RAW264.7 murine macrophages expressing a luciferase reporter gene were injected into the systemic circulation. Quantification of bioluminescence showed that NF-κB decoy ODN reduced the homing of these reporter macrophages into the distal femurs exposed to continuous particle delivery. Particle-induced reduction in bone mineral density at the distal diaphysis of the femur was also mitigated by infusion of decoy ODN. Histological staining showed that the decoy ODN infusion decreased osteoclast and macrophage numbers, but had no significant effects on osteoblasts. Local infusion of NF-κB decoy ODN reduced systemic macrophage infiltration and mitigated particle-induced bone loss, thus providing a potential strategy to treat periprosthetic osteolysis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3169-3175, 2017. [ABSTRACT FROM AUTHOR]