Search

Purpose Interferon (IFN)-γ is a major cytokine produced by immune cells that plays diverse roles in modulating both the immune system and bone metabolism, but its role in autogenous bone grafting remains unknown. Here, we present that local IFN-γ administration improved the efficacy of autogenous bone graft treatment in an experimental rat model. Methods An autogenous bone graft model was prepared with critically sized rat calvariae defects. Four weeks (w) after bone graft implantation, rats were treated locally with IFN-γ or were not treated. The effect of IFN-γ on bone formation was evaluated for up to 8 w with micro-computed tomography, quantitative histomorphometry, and Von Kossa staining. Osteoclastogenesis was assessed by tartrate-resistant acid phosphatase staining. Immunohistochemistry staining or quantitative polymerase chain reactions were used to estimate the expression of osteoclast differentiation factor and inflammatory cytokines including tumor necrosis factor (TNF)-α, a well-known stimulant of osteoclastogenesis and an inhibitor of osteoblast activity, in defects. Results Newly formed bone gradually replaced the autogenous bone grafts within 4 w, although severe bone resorption with osteoclastogenesis and TNF-α expression occurred after 6 w in the absence of IFN-γ administration. IFN-γ administration markedly attenuated bone loss, osteoclastogenesis, and TNF-α expression, while it enhanced bone formation at 8 w. Conclusion Local IFN-γ administration promoted bone formation in autogenous bone grafts possibly via regulating osteoclastogenesis and TNF-α expression. The data provide insights into the potential roles of IFN-γ in autogenous bone grafting. [ABSTRACT FROM AUTHOR]

Various stresses latently induce cellular senescence that occasionally deteriorates the functioning of surrounding tissues. Nevertheless, little is known about the appearance and function of senescent cells, caused by the implantation of beta-tricalcium phosphate (β-TCP)—used widely in dentistry and orthopedics for treating bone diseases. In this study, two varying sizes of β-TCP granules (<300 μm and 300–500 μm) were implanted, and using histological and immunofluorescent staining, appearances of senescent-like cells in critical-sized bone defects in the calvaria of Sprague Dawley rats were evaluated. Parallelly, bone formation in defects was investigated with or without the oral administration of senolytics (a cocktail of dasatinib and quercetin). A week after the implantation, the number of senescence-associated beta-galactosidase, p21-, p19-, and tartrate-resistant acid phosphatase-positive cells increased and then decreased upon administrating senolytics. This administration of senolytics also attenuated 4-hydroxy-2-nonenal staining, representing reactive oxygen species. Combining senolytic administration with β-TCP implantation significantly enhanced the bone formation in defects as revealed by micro-computed tomography analysis and hematoxylin-eosin staining. This study demonstrates that β-TCP granules latently induce senescent-like cells, and senolytic administration may improve the bone-forming ability of β-TCP by inhibiting senescence-associated mechanisms. [ABSTRACT FROM AUTHOR]

Stress-induced premature senescent (SIPS) cells induced by various stresses deteriorate cell functions. Dasatinib and quercetin senolytics (DQ) can alleviate several diseases by eliminating senescent cells. α-tricalcium phosphate (α-TCP) is a widely used therapeutic approach for bone restoration but induces bone formation for a comparatively long time. Furthermore, bone infection exacerbates the detrimental prognosis of bone formation during material implant surgery due to oral cavity bacteria and unintentional contamination. It is essential to mitigate the inhibitory effects on bone formation during surgical procedures. Little is known that DQ improves bone formation in Lipopolysaccharide (LPS)-contaminated implants and its intrinsic mechanisms in the study of maxillofacial bone defects. This study aims to investigate whether the administration of DQ ameliorates the impairments on bone repair inflammation and contamination by eliminating SIPS cells. α-TCP and LPS-contaminated α-TCP were implanted into Sprague-Dawley rat calvaria bone defects. Simultaneously, bone formation in the bone defects was investigated with or without the oral administration of DQ. Micro-computed tomography and hematoxylin-eosin staining showed that senolytics significantly enhanced bone formation at the defect site. Histology and immunofluorescence staining revealed that the levels of p21- and p16-positive senescent cells, inflammation, macrophages, reactive oxygen species, and tartrate-resistant acid phosphatase-positive cells declined after administering DQ. DQ could partially alleviate the production of senescent markers and senescence-associated secretory phenotypes in vitro. This study indicates that LPS-contaminated α-TCP-based biomaterials can induce cellular senescence and hamper bone regeneration. Senolytics have significant therapeutic potential in reducing the adverse osteogenic effects of biomaterial-related infections and improving bone formation capacity. [Display omitted] • LPS-contaminated biomaterials induce cellular senescence and impede bone regeneration. • Senolytics reduce senescent cells and adverse osteogenic effects. • Senolytics may enhance bone formation in infections associated with biomaterial implantation. [ABSTRACT FROM AUTHOR]