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Aseptic inflammation is a major cause of late failure in total joint arthroplasty, and the primary factor contributing to the development and perpetuation of aseptic inflammation is classical macrophage activation (M1 phenotype polarization) induced by wear particles. CD73 (ecto-5'-nucleotidase) is an immunosuppressive factor that establishes an adenosine-induced anti-inflammatory environment. Although CD73 has been shown to suppress inflammation by promoting alternate macrophage activation (M2 phenotype polarization), its role in wear particle-induced aseptic inflammation is currently unknown. Our experiments were based on metabolomic assay results in a mouse model of aseptic loosening, and studied the function of CD73 in vivo and in vitro using a mouse aseptic loosening model and a mouse bone marrow derived macrophage (BMDM) inflammation model. Results show that aseptic loosening (AL) reduces the purine metabolic pathway and decreases the native expression of the metabolite adenosine. In vivo, CD73 expression was low in the bone tissue surrounding the titanium nail and synovial-like interface tissue, while in vitro experiments demonstrated that CD73 knockdown promoted titanium particles-induced aseptic inflammation. CD73 overexpression mitigated the titanium particle-mediated enhancement of LPS-induced M1 polarization while promoting the titanium particle-mediated attenuation of IL-4-induced M2 polarization. In BMDM exposed to titanium particles, CD73 promotes M2 polarization via the p38 pathway. Meanwhile, local injection of recombinant mouse CD73 protein slightly alleviated the progression of AL. Collectively, our data suggest that CD73 alleviates the process of AL, and this function is achieved by promoting alternate activation of macrophages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To explore the feasibility of establishment of a artificial joint aseptic loosening mouse model by cobalt-chromium particles stimulation., Methods: Twenty-four 8-week-old male severe combined immunodeficient (SCID) mice were divided into experimental group ( n =12) and control group ( n =12). The titanium nail was inserted into the tibial medullary cavity of mouse in the two groups to simulate artificial joint prosthesis replacement. And the cobalt-chromium particles were injected into the tibial medullary cavity of mouse in experimental group. The survival of the mouse was observed after operation; the position of the titanium nail and the bone mineral density of proximal femur were observed by X-ray film, CT, and Micro-CT bone scanning; and the degree of dissolution of the bone tissue around the tibia was detected by biomechanical test and histological staining., Results: Two mice in experimental group died, and the rest of the mice survived until the experiment was completed. Postoperative imaging examination showed that there was no obvious displacement of titanium nails in control group, and there were new callus around the titanium nails. In experimental group, there was obvious osteolysis around the titanium nails. The bone mineral density of the proximal tibia was 91.25%±0.67%, and the maximum shear force at the tibial nail-bone interface was (5.93±0.85) N in experimental group, which were significantly lower than those in control group [102.07%±1.87% and (16.76±3.09) N] ( t =5.462, P =0.041; t =3.760, P =0.046). Histological observation showed that a large number of inflammatory cells could be seen around the titanium nails in experimental group, while there was no inflammatory cells, and obvious bone tissue formation was observed in control group., Conclusion: The artificial joint aseptic loosening mouse model can be successfully established by cobalt-chromium particles stimulation.

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 × 10 5 ) 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., (© 2018 Wiley Periodicals, Inc.)

This study investigated the therapeutic influence and potential mechanism of IL-10 in ameliorating orthopedic debris particle-induced inflammation and osteolysis. A murine air pouch with bone implantation and polyethylene particles was also used to evaluate the therapeutic effects of IL-10. The data suggested that the particle challenges significantly promoted macrophage activation and osteoclastogenesis, with dramatically increased macrophage infiltration into the pouch membranes and elevated tartrate-resistant acid phosphatase-positive cell deposition. Immunohistochemical stains revealed a significantly higher ratio of induced nitric oxide synthase-expressing cells in the particle-challenged group; treatment with IL-10 resulted in marked switching to CD163(+) cells. Also, IL-10 effectively reduced tartrate-resistant acid phosphatase-positive stained cells in the pouch membranes, and minimized the bone mineral density loss compared with untreated samples. Real-time PCR and Western blot examination indicated that IL-10 treatment significantly diminished the particle-induced IL-1β expression but promoted expression of CD163, transforming growth factor-β1, and CCR2. Furthermore, IL-10 significantly inhibited the ultra-high-molecular-weight polyethylene particle-elevated phospho-STAT1 and phospho-NF-κB p65 productions, and promoted phospho-STAT3 expression. Overall, the data indicate the pivotal effects of IL-10 on macrophage polarization. The effects of IL-10 in ameliorating local inflammation and osteolysis may be associated with macrophage polarization through the up-regulation of the Janus activating kinase/STAT3 signaling pathway, and the down-regulation of NF-κB and Janus activating kinase/STAT1 expression., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)