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Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis.

ABSTRACT: Cell senescence is a chronic process associated with age-related degenerative diseases such as osteoarthritis (OA). Senescent cells (SnCs) accumulate in the articular cartilage and synovium, leading to OA pathologies. The accumulation of SnCs in the cartilage results in a senescence-associated secretory phenotype (SASP) and age-related inflammation and dysfunction. Selective removal of SnCs by senolytic agent as a therapeutic strategy has been developed recently. In this study, we examined the ability of the senolytic drug ABT263 (navitoclax) to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic OA. Monolayer and 3D pellet cultured osteoarthritic chondrocytes were used to evaluate the effect of ABT263 in vitro and a DMM rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation in OA chondrocyte pellet culture by inducing SnC apoptosis. Moreover, OA pathological changes in the cartilage and subchondral bone in post-traumatic OA rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance in vitro. Furthermore, ABT263 might play a protective role against post-traumatic OA development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of OA.

SUBMITTER: Yang H

PROVIDER: S-EPMC7377880 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis.

Yang Hao H Chen Cheng C Chen Hao H Duan Xiaojun X Li Juan J Zhou Yi Y Zeng Weinan W Yang Liu L

Aging 20200701 13

Cell senescence is a chronic process associated with age-related degenerative diseases such as osteoarthritis (OA). Senescent cells (SnCs) accumulate in the articular cartilage and synovium, leading to OA pathologies. The accumulation of SnCs in the cartilage results in a senescence-associated secretory phenotype (SASP) and age-related inflammation and dysfunction. Selective removal of SnCs by senolytic agent as a therapeutic strategy has been developed recently. In this study, we examined the a ...[more]

PMID: 32611834

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Project description:IntroductionAutologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA.MethodsArticular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score > 3, Ahlbäck Score > 2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using real-time PCR.ResultsChondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (ACAN, COL2A1, COMP, CRTL1, SOX9) and genes involved in matrix synthesis (BGN, CILP2, COL9A2, COL11A1, TIMP4) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (ALPL, COL1A1, COL3A1, COL10A1, MMP13, POSTN, PTH1R, RUNX2) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, was differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated.ConclusionsOnly few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA, and OA chondrocytes fulfill the requirements for matrix-associated ACT.

Project description:BackgroundOsteoarthritis is a degenerative joint disease. Cartilage degeneration is the earliest and most important pathological change in osteoarthritis, and persistent inflammation is one of the driving factors of cartilage degeneration. Cucurbitacin E, an isolated compound in the Cucurbitacin family, has been shown to have anti-inflammatory effects, but its role and mechanism in osteoarthritic chondrocytes are unclear.MethodsFor in vitro experiments, human chondrocytes were stimulated with IL-1β, and the expression of inflammatory genes was measured by Western blotting and qPCR. The expression of extracellular matrix proteins was evaluated by immunofluorescence staining, Western blotting and saffron staining. Differences in gene expression between cartilage from osteoarthritis patients and normal cartilage were analysed by bioinformatics methods, and the relationship between Cucurbitacin E and its target was analysed by a cellular thermal shift assay, molecular docking analysis and molecular dynamics simulation. For in vivo experiments, knee osteoarthritis was induced by DMM in C57BL/6 mouse knee joints, and the effect of Cucurbitacin E on knee joint degeneration was evaluated.ResultsThe in vitro experiments confirmed that Cucurbitacin E effectively inhibited the production of the inflammatory cytokine interleukin-1β(IL-1β) and cyclooxygenase-2 (COX-2) by IL-1β-stimulated chondrocytes and alleviates extracellular matrix degradation. The in vivo experiments demonstrated that Cucurbitacin E had a protective effect on the knee cartilage of C57BL/6 mice with medial meniscal instability in the osteoarthritis model. Mechanistically, bioinformatic analysis of the GSE114007 and GSE117999 datasets showed that the PI3K/AKT pathway was highly activated in osteoarthritis. Immunohistochemical analysis of PI3K/Akt signalling pathway proteins in pathological slices of human cartilage showed that the level of p-PI3K in patients with osteoarthritis was higher than that in the normal group. PI3K/Akt were upregulated in IL-1β-stimulated chondrocytes, and Cucurbitacin E intervention reversed this phenomenon. The cellular thermal shift assay, molecular docking analysis and molecular dynamics experiment showed that Cucurbitacin E had a strong binding affinity for the inhibitory target PI3K. SC79 activated Akt phosphorylation and reversed the effect of Cucurbitacin E on IL-1β-induced chondrocyte degeneration, demonstrating that Cucurbitacin E inhibits IL-1β-induced chondrocyte inflammation and degeneration by inhibiting the PI3K/AKT pathway.ConclusionCucurbitacin E inhibits the activation of the PI3K/AKT pathway, thereby alleviating the progression of OA. In summary, we believe that Cucurbitacin E is a potential drug for the treatment of OA.

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Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis.

Publications

Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis.

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