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.

Ning Zhang,Masaya Ueno,Ejun Huang,Claire Rhee,Zhenyu Yao,Yusuke Kohno,Tzuhua Lin,Takeshi Utsunomiya,Masahiro Maruyama,Stuart B Goodman

doi:10.3389/fcell.2021.757830

Ning Zhang, Masaya Ueno + Show 8 more

Open Access

https://doi.org/10.3389/fcell.2021.757830

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Abstract

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (μCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

Highlights

Wear particles from total joint arthroplasties (TJAs) incite a persistent macrophage-mediated chronic inflammatory reaction resulting in the release of cytokines, chemokines, and other molecules (Bi et al, 2001; Xu et al, 2009; Abu-Amer, 2013) and, stimulate key paracrine and autocrine cell interactions (Goodman et al, 2013)
The BMD in the region of interest (ROI) (Figure 2A) of the contaminated particles (cPE) + control group was significantly reduced compared with the BMD of the Chronic inflammation around implants due to byproducts of wear or other causes is still a major an unsolved problem
We have demonstrated that local delivery of contaminated polyethylene particles can induce acute or chronic inflammation and polarize macrophages to a pro-inflammatory M1 rather than an anti-inflammatory M2 macrophage phenotype in different in vitro and in vivo models (Utsunomiya et al, 2021a,b)

Summary

Introduction

Wear particles from total joint arthroplasties (TJAs) incite a persistent macrophage-mediated chronic inflammatory reaction resulting in the release of cytokines, chemokines, and other molecules (Bi et al, 2001; Xu et al, 2009; Abu-Amer, 2013) and, stimulate key paracrine and autocrine cell interactions (Goodman et al, 2013). This reaction promotes bone resorption and impedes bone formation, leading to periprosthetic osteolysis and eventually, loss of mechanical support for the implant (Goodman, 2007; Goodman et al, 2014; Qiu et al, 2020). We test whether NF-κB sensing IL-4 over-expressing MSC treatment is a more efficacious therapeutic strategy than unaltered MSCs for particle induced chronic inflammatory bone loss in this model

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