{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPSTPIP2 is an adaptor protein that plays a central role in preventing autoinflammatory bone disorders. Studies in mouse models have shown that loss‐of‐function mutations in PSTPIP2 result in uncontrolled inflammatory responses manifesting as chronic multifocal osteomyelitis and related syndromes. Deficiency of this protein leads to abnormal activation and expansion of macrophage precursors as well as enhanced IL‐1β production by neutrophils, altogether promoting inflammation and bone lesions. Moreover, in syndromes with sterile inflammation such as SAPHO, an impaired regulatory function of PSTPIP2 contributes to the persistence of inflammatory stimuli."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn myeloid cells, PSTPIP2 exerts its inhibitory influence on key signaling pathways that regulate osteoclast differentiation and cytokine production. By modulating CSF-1 receptor signaling and interacting with molecules such as PEST-family phosphatases and SHIP1, PSTPIP2 suppresses the fusion and differentiation of osteoclast precursors and dampens excessive production of proinflammatory mediators like IL-1β and MIP-1α. Furthermore, defects in PSTPIP2 function lead to dysregulated actin dynamics––notably at podosomes––which correlate with enhanced cell motility, exaggerated matrix degradation, and ultimately contribute to pathological bone resorption."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in bone homeostasis, PSTPIP2 influences broader inflammatory and fibrotic processes. Aberrant expression or epigenetic silencing of PSTPIP2 has been implicated in the misregulation of macrophage polarization––with shifts in the balance between M1 and M2 phenotypes––thereby exacerbating tissue inflammation and fibrosis, as seen in hepatic fibrosis models. Moreover, by negatively regulating NADPH oxidase activity, PSTPIP2 helps to limit reactive oxygen species production, underscoring its importance in restraining inflammatory tissue damage. Collectively, these findings position PSTPIP2 as a key negative regulator of both innate immune activation and osteoclast-mediated bone resorption."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, et al. 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