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Multiple studies have demonstrated that dysregulated inflammatory environments caused by macrophage activation and aberrant differentiation of FAPs are critical factors contributing to disease progression. However, the specific mechanisms mediating functional changes between these two cell types during NHO remain unclear. This study found that FAPs aggregate, proliferate, and undergo osteogenic differentiation in the pathological bone regions of NHO. Differential gene expression analysis in an NHO mouse model has shown that the OPN expression is elevated in muscles which develop NHO. Using techniques such as flow cytometry sorting with immunofluorescence staining, it has been shown that the primary cellular source of osteopontin (OPN) is the M2 macrophage (M2). The up\u2010regulation of OPN expression is primarily controlled by the transcription factor NFKB2 within the macrophage. 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