Overexpression of secretory leukocyte peptidase inhibitor (SLPI) does not modulate experimental osteoarthritis but may be a biomarker for the disease

Kim, H.-E.; Shin, Younghak; Jung, In‐Ha; Yang, Jamie O.; Chun, Churl Hong; Kim, H.A.; Chun, Jang‐Soo

doi:10.1016/j.joca.2021.01.003

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…Human OA cartilage ( n = 5) was sourced from individuals undergoing arthroplasty [ 14 , 15 ]. Characteristics of individuals with OA from whom cartilage samples were taken were presented in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

STING mediates experimental osteoarthritis and mechanical allodynia in mouse

et al. 2023

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Background This study was performed to develop therapeutic targets of osteoarthritis (OA) that can be targeted to alleviate OA development (i.e., cartilage destruction) and relieve the OA-associated joint pain. Methods The candidate molecule, STING (stimulator of interferon genes, encoded by Sting1), was identified by microarray analysis of OA-like mouse chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). STING functions in OA and hindpaw mechanical allodynia were evaluated by gain-of-function (intra-articular injection of a STING agonist) and loss-of-function (Sting1−/− mice) approaches. Results DNA damage was observed in OA-like chondrocytes. Cytosolic DNA sensors, STING and its upstream molecule, cGAS (cyclic GMP-AMP synthase), were upregulated in OA chondrocytes and cartilage of mouse and human. Genetic ablation of STING in mice (Sting1−/−) alleviated OA manifestations (cartilage destruction and subchondral bone sclerosis) and hindpaw mechanical allodynia. In contrast, stimulation of STING signaling in joint tissues by intra-articular injection of cGAMP exacerbated OA manifestations and mechanical sensitization. Mechanistic studies on the regulation of hindpaw mechanical allodynia revealed that STING regulates the expression of peripheral sensitization molecules in the synovium and meniscus of mouse knee joints. Conclusion Our results indicated that STING, which senses damaged cytosolic DNA and accordingly activates the innate immune response, regulates OA pathogenesis and hindpaw mechanical allodynia. Therefore, inhibition of STING could be a therapeutic approach to inhibit OA cartilage destruction and relieve the associated mechanical sensitization in model mice.

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Section: Methodsmentioning

confidence: 99%

STING mediates experimental osteoarthritis and mechanical allodynia in mouse

et al. 2023

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“…BMPCa patients are prone to fractures and bone pain due to activation of abnormal bone metabolic pathways. Secretory leukocyte peptidase inhibitor (SLPI) is a highly upregulated inhibitor of cellular proteases that protects HIF-2-alpha (2 α )-treated chondrocytes from inflammatory responses ( Kim et al, 2021 ). In addition, SLPI active reticulum-like structures (a mixture of SLPI with neutrophil DNA and NE) stimulate the synthesis of type I interferon (IFNI) synthesis in plasmacytoid dendritic cells (pDCs) in vitro to regulate organismal immunity ( Majewski et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring the role of differentially expressed metabolic genes and their mechanisms in bone metastatic prostate cancer

Zhang

Zhao

et al. 2023

PeerJ

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Background Approximately 10–20% of patients diagnosed with prostate cancer (PCa) evolve into castration-resistant prostate cancer (CRPC), while nearly 90% of patients with metastatic CRPC (mCRPC) exhibit osseous metastases (BM). These BM are intimately correlated with the stability of the tumour microenvironment. Purpose This study aspires to uncover the metabolism-related genes and the underlying mechanisms responsible for bone metastatic prostate cancer (BMPCa). Methods Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets of PCa and BM were analyzed through R Studio software to identify differentially expressed genes (DEGs). The DEGs underwent functional enrichment via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), with key factors screened by a random forest utilized to establish a prognostic model for PCa. The study explored the relationship between DEGs and the stability of the immune microenvironment. The action and specificity of CRISP3 in PCa was validated through western blot analysis, CCK-8 assay, scratch assay, and cellular assay. Results The screening of GEO and TCGA datasets resulted in the identification of 199 co-differential genes. Three DEGs, including DES, HBB, and SLPI, were selected by random forest classification model and cox regression model. Immuno-infiltration analysis disclosed that a higher infiltration of naïve B cells and resting CD4 memory T cells occurred in the high-expression group of DES, whereas infiltration of resting M1 macrophages and NK cells was greater in the low-expression group of DES. A significant infiltration of neutrophils was observed in the high-expression group of HBB, while greater infiltration of gamma delta T cells and M1 macrophages was noted in the low-expression group of HBB. Resting dendritic cells, CD8 T cells, and resting T regulatory cells (Tregs) infiltrated significantly in the high-expression group of SLPI, while only resting mast cells infiltrated significantly in the low-expression group of SLPI. CRISP3 was established as a critical gene in BMPCa linked to DES expression. Targeting CRISP3, d-glucopyranose may impact tumour prognosis. During the mechanistic experiments, it was established that CRISP3 can advance the proliferation and metastatic potential of PCa by advancing epithelial-to-mesenchymal transition (EMT). Conclusion By modulating lipid metabolism and maintaining immunological and microenvironmental balance, DES, HBB, and SLPI suppress prostate cancer cell growth. The presence of DES-associated CRISP3 is a harbinger of unfavorable outcomes in prostate cancer and may escalate tumor proliferation and metastatic capabilities by inducing epithelial-mesenchymal transition.

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“…Human OA cartilage and experimental OA in mice Human OA cartilage (n = 5) was sourced from individuals undergoing arthroplasty [14,15]. The Institutional Review Board of Wonkwang University Hospital approved the use of these materials, and all participants provided written informed consent before the operative procedure.…”

Section: Methodsmentioning

confidence: 99%

“…1). Mice were sacri ced at 6 or 8 weeks after DMM surgery and subjected to histological analyses based on the previous experiments [7,8,14,15]. To stimulate STING signaling in joint tissues, 12-week-old male C57BL/6J mice were IA injected once a week with cyclic GMP-AMP (cGAMP; 10 or 20 µg in 10 µl PBS) [17] for 3 weeks, and sacri ced at 3 or 8 weeks after the rst IA injection.…”

Section: Methodsmentioning

confidence: 99%

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STING mediates experimental osteoarthritis and the associated pain behavior in mouse

Shin

Cho

Kim

et al. 2022

Preprint

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Background. This study was performed to develop therapeutic targets of osteoarthritis (OA) that can be targeted to alleviate OA development (i.e., cartilage destruction) and relieve the OA-associated joint pain. Methods: The candidate molecule, STING (stimulator of interferon genes, encoded by Sting1), was identified by microarray analysis of OA-like mouse chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). STING functions in OA and joint pain were evaluated by gain-of-function (intra-articular injection of a STING agonist) and loss-of-function (Sting1-/- mice) approaches. Results: DNA damage was observed in OA-like chondrocytes. Cytosolic DNA sensors, STING and its upstream molecule, cGAS (cyclic GMP-AMP synthase), were upregulated in OA chondrocytes and cartilage of mouse and human. Genetic ablation of STING in mice (Sting1-/-) alleviated OA manifestations (cartilage destruction and subchondral bone sclerosis) and OA-associated pain behavior. In contrast, stimulation of STING signaling in joint tissues by intra-articular injection of cGAMP exacerbated OA manifestations and pain behavior. Mechanistic studies on the regulation of OA pain revealed that STING regulates the expression of peripheral sensitization molecules in the synovium and meniscus of mouse knee joints. Conclusion: Our results indicated that the cGAS-STNG pathway in chondrocytes, which senses damaged cytosolic DNA and accordingly activates the innate immune response, regulates OA pathogenesis and joint pain. Therefore, inhibition of STING could be a therapeutic approach to inhibit OA cartilage destruction and relieve the associated pain in model mice.

show abstract

Overexpression of secretory leukocyte peptidase inhibitor (SLPI) does not modulate experimental osteoarthritis but may be a biomarker for the disease

Cited by 8 publications

References 38 publications

STING mediates experimental osteoarthritis and mechanical allodynia in mouse

STING mediates experimental osteoarthritis and mechanical allodynia in mouse

Exploring the role of differentially expressed metabolic genes and their mechanisms in bone metastatic prostate cancer

STING mediates experimental osteoarthritis and the associated pain behavior in mouse

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