Pstpip2-deficient mouse models in SAPHO syndrome research: Utility, mechanistic insights, and translational...

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare autoinflammatory disorder characterized by combined cutaneous and osteoarticular involvement. Its etiology and pathogenesis remain incompletely understood, and an ideal animal model capable of fully recapitulating its phenotype is still lacking. Pstpip2-deficient mice exhibit sterile osteitis, inflammatory bone destruction, abnormal bone remodeling, and varying degrees of extraosseous inflammation, accompanied by myeloid immune abnormalities and IL-1β-associated inflammatory dysregulation. These mice have therefore become an important experimental model for investigating SAPHO-related myeloid inflammation and inflammatory bone remodeling. This review focuses on the biological functions of Pstpip2 and the different models of Pstpip2 deficiency, systematically summarizing the major model types and disease-course characteristics, osteoarticular and cutaneous phenotypes, systemic myeloid inflammation, and mechanisms involving aberrant neutrophil activation, IL-1β production and processing, osteoclast differentiation, abnormal bone formation, and the functional division between hematopoietic and non-hematopoietic compartments. We also discuss the effects of breeding efficiency, genetic background, diet, and gut microbiota on phenotypic stability, as well as the translational value and limitations of current therapeutic targets and pharmacological intervention evidence. However, Pstpip2 has not been established as a definitive causative gene for human SAPHO syndrome, and these models remain limited in terms of lesion distribution, the extent to which hyperostosis is reproduced, and phenotypic stability. Therefore, Pstpip2-deficient mice are better regarded as mechanistic models of SAPHO-related myeloid inflammation and inflammatory bone remodeling rather than as fully homologous surrogates for the human disease.