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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]

The naked mole-rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled 'Surprisingly long survival of premature conclusions about naked mole-rat biology' described 28 'myths' which, those authors claimed, are a 'perpetuation of beautiful, but falsified, hypotheses' and impede our understanding of this enigmatic mammal. Here, we re-examine each of these 'myths' based on evidence published in the scientific literature. Following Braude et al., we argue that these 'myths' fall into four main categories: (i) 'myths' that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) 'myths' that are based on incomplete understanding, where more evidence is clearly needed; (iii) 'myths' where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) 'myths' where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term 'myth' is particularly inappropriate when applied to competing, evidence-based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole-rat biology and attempt to clarify some of these misconceptions., (© 2021 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

Titanium and titanium-based alloys are widely used in orthopaedic implants. Total joint replacement is very successful; however, the foreign body response and chronic inflammation caused by implant-derived biomaterial debris still remain as unsolved issues. Aseptic loosening accompanied by wear debris-induced osteolysis (bone loss) is one of the most frequent causes for late failure and revision surgery. Mesenchymal stem cells (MSCs) and IL-4 may be possible treatment strategies because of their immunomodulatory properties. We investigated the efficacy of novel MSC-based treatments on immunomodulation and osteogenic differentiation in an innovative cell coculture model of titanium particle-induced inflammation in the periprosthetic tissues. MSCs and macrophages were collected from the bone marrow of Balb/c mice. Both MSCs and macrophages (representing endogenous cells at the periprosthetic tissue) were seeded on the bottom wells of the 24-well transwell plates. We generated genetically modified NF- κ B sensing IL-4 secreting MSCs (inflammatory responsive MSCs) and MSCs preconditioned by lipopolysaccharide and TNF- α to further enhance their immunomodulatory function. These modified MSCs (representing exogenous therapeutic cells implanted to the periprosthetic tissue) were seeded on the upper chambers of the transwell plates. These cocultures were then exposed to titanium particles for 7 days. NF- κ B sensing IL-4 secreting MSCs showed strong immunomodulation (significantly reduced TNF- α and induced Arg1 expression) and promoted early osteogenesis (significantly induced Runx2, ALP, and β -catenin as well as reduced Smurf2 expression) at day 7. IL-4 secreting MSCs also decreased TNF- α protein secretion as early as day 3 and increased IL-1ra protein secretion at day 7, suggesting efficacious immunomodulation of particle-induced inflammation. Preconditioned MSCs did not show significant immunomodulation in this short-term experiment, but ALP and β -catenin expression were significantly induced at day 7. Our results suggest that genetically modified IL-4 secreting MSCs and preconditioned MSCs have the potential to optimize bone regeneration in inflammatory conditions including periprosthetic osteolysis., Competing Interests: The authors declare no competing financial interest.

Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen-associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-γ plus TNF-α restimulation-induced iNOS expression as a model of MSC activation, because IFN-γ and TNF-α play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-α, IL-1β, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.