The difficulties associated with metal implants and soft tissue integration have significantly affected the applications of metal implants in soft-tissue-related areas. Prompted by the close association between soft tissue integration and the immune response, an immunomodulation-based strategy is proposed to manipulate the immune microenvironment and improve metal implantsoft tissue integration. Considering their vital roles in soft tissue responses to metal implants, macrophages are used and the cytokines fingerprints of M1 and M2 macrophage immune microenvironments are evaluated for their potential modulatory effects on metal implant-soft tissue integration. The modulatory effects of different immune microenvironments on model soft tissue cells (human gingival epithelium cells) cultured on model metal implants (titanium alloy disks) are then described, with the underlying possible mechanism FAK-AKT-mTOR signaling unveiled. As further proof of concept, IL-4/PDA (polydopamine)-coated titanium alloy implants, aiming at modulating M2 macrophage polarization, are prepared and found to improve the in vivo metal implant-soft tissue integration. It is the authors' ambition that this immunomodulation-based strategy will change the negative perception and encourage the active development of metal materials with favorable soft tissue integration properties, thus improving the success rates of perforating metal implants and broadening their application in soft-tissue-related areas.

The immune and skeletal systems share common mechanisms, and the crosstalk between the two has been termed osteoimmunology. Osteoimmunology mainly focuses on diseases between the immune and bone systems including bone loss diseases, and imbalances in osteoimmune regulation affect skeletal homeostasis between osteoclasts and osteoblasts. The immune mediator interleukin‐20 (IL‐20), a member of the IL‐10 family, enhances inflammation, chemotaxis and angiogenesis in diseases related to bone loss. However, it is unclear how IL‐20 regulates the balance between osteoclastogenesis and osteoblastogenesis; therefore, we explored the mechanisms by which IL‐20 affects bone mesenchymal stem cells (BMSCs) in osteoclastogenesis in primary cells during differentiation, proliferation, apoptosis and signalling. We initially found that IL‐20 differentially regulated preosteoclast proliferation and apoptosis; BMSC‐conditioned medium (CM) significantly enhanced osteoclast formation and bone resorption, which was dose‐dependently regulated by IL‐20; IL‐20 inhibited OPG expression and promoted M‐CSF, RANKL and RANKL/OPG expression; and IL‐20 differentially regulated the expression of osteoclast‐specific gene and transcription factors through the OPG/RANKL/RANK axis and the NF‐kB, MAPK and AKT pathways. Therefore, IL‐20 differentially regulates BMSCs in osteoclastogenesis and exerts its function by activating the OPG/RANKL/RANK axis and the NF‐κB, MAPK and AKT pathways, which make targeting IL‐20 a promising direction for targeted regulation in diseases related to bone loss.

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