Repeated Mesenchymal Stem Cell Delivery Attenuates UHMWPE Wear Particle-Induced Osteolysis by Paracrine-Mediated Macrophage Reprogramming.

PURPOSE: Periprosthetic osteolysis (PPO) induced by ultra-high molecular weight polyethylene (UHMWPE) particles remains a major clinically challenging problem in joint arthroplasty. This study investigated whether local delivery of bone marrow mesenchymal stem cells (BMSCs) could alleviate UHMWPE-induced bone destruction by modulating macrophage polarization.

METHODS

In vivo, a murine calvarial osteolysis model was established and divided into four groups: Sham, UHMWPE-induced osteolysis (PIO), single BMSC injection (BMSCs-1), and repeated BMSC injection (BMSCs-2) groups. In vitro, RAW264.7 macrophages were treated under five conditions: RAW264.7 alone, BMSCs alone, RAW264.7+BMSCs, RAW264.7 + UHMWPE, and RAW264.7 + UHMWPE + BMSCs in a transwell co-culture system. Bone parameters (BMD, BV/TV, Tb.Th, and Tb.N) were evaluated by micro-CT; Macrophage polarization and cytokine expression were assessed by histology, immunohistochemistry (IHC), flow cytometry, ELISA, and immunofluorescence.

RESULTS

In vivo, BMSC administration markedly improved bone parameters and mitigated UHMWPE-induced osteolysis, with repeated dosing showing more efficacy than a single dose compared to the PIO group. BMSC treatment suppressed M1 (CD80⁺) macrophage infiltration, enhanced M2 (CD206⁺) polarization, and rebalanced cytokine expression by reducing TNF-α and increasing IL-10 levels. In vitro, the BMSC transwell co-culture system consistently promoted M2 polarization and anti-inflammatory cytokine secretion in UHMWPE-stimulated macrophages, confirming the paracrine-mediated immunomodulatory effect.

CONCLUSION

Local BMSC therapy, particularly with repeated dosing, effectively attenuated UHMWPE-induced osteolysis by reprogramming macrophage polarization through paracrine signaling. These findings highlight a potential translational strategy for stem cell-based treatment of periprosthetic osteolysis.