Benzophenone-3 drives osteoarthritis pathogenesis by regulating chondrocyte senescence.

Mechanism of chondrocyte injury induced by Benzophenone-3 through modulation of the IL-6/JAK2/STAT3 pathway.

Integrated analysis of the transcriptome and proteome reveals that ABI3BP is involved in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is driven by chronic low-grade inflammation and subsequent cartilage degradation. OA is the most prevalent degenerative joint disease worldwide, and its treatment remains a challenge. The aim of this study was to explore the potential effects and mechanism underlying the anti-OA properties of ginkgolide C (GC). Protective effects of GC on hydrogen peroxide (H2O2)-treated rat chondrocytes were evaluated using ELISA, qPCR, western blot analysis, flow cytometry, ROS detection and immunofluorescence in vitro. Ameliorating effects of GC on cartilage degeneration in rats were evaluated through behavioral assays, microcomputed tomography, histopathological analysis, western blot analysis and ELISA in vivo. In vitro, GC treatment inhibited the release of pro-apoptotic factors induced by H2O2 and promoted the release of the anti-apoptotic proteins. In addition, GC decreased the expression of matrix metalloproteinase (MMP3 and MMP13), thrombospondin motifs 4 (ADAMTS4), and inflammatory mediators inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and SOX9 thereby inhibiting extracellular matrix (ECM) degradation. Mechanistically, GC exerts its anti-apoptotic and anti-inflammatory effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, In a rat model with post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT), GC inhibited joint pain, cartilage destruction, and abnormal bone remodeling of subchondral bone. GC inhibited H2O2-induced chondrocyte apoptosis through Nrf2/HO-1 and NF-κB axis, exerted anti-inflammatory effects, and inhibited cartilage degeneration in rat OA. Our findings advanced the concept that GC may contribute to cartilage metabolism through anti-inflammatory and anti-apoptotic effects, and the identified GC is a potential therapeutic agent for the treatment of OA.

Introduction: Experimental studies have suggested endocrine disruption by BP-3, an active ingredient in sunscreen, with widespread exposure around the world. Methods: We recruited girls ages 6 - 8 years who returned semi-annually for pubertal maturation staging (thelarche, pubarche), to provide blood for serum hormone assay [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine for BP-3 assay. Parents completed yearly questionnaires on participant’s past-year sunscreen use and attainment of menarche. Quantile regression determined the relationship between each log-transformed sex hormone with BP-3 exposure, measured by either biomarker (with half-life of 16 hours) or sunscreen questionnaire (use over the last year). Cox-proportional hazards models examined whether higher quartile of BP-3 exposure was associated with age-of-pubertal milestone. Results: The median value of baseline BP-3 measurements was 25.0 μg/g-creatinine (N=353), with detection in 98.9% of samples. The median number of days sunscreen was used in the past year was 48 days (N=302). There was no evidence of associations between any of the four hormones and the BP-3 biomarker. Testosterone, measured at the time of thelarche, was inversely associated with sunscreen use by questionnaire data (N=157, adjusted β= -0.0163, 97.5%CI: -0.0300, -0.0026). There was no evidence of association between sunscreen use by questionnaire and testosterone during other time windows (-6 months and +6 months) or other hormones at any time points. Age-of-Thelarche was later among participants in the 2nd quartile of BP-3 biomarker compared to the 1st quartile (N=282, adjusted HR=1.5900, 97.5%CI:1.0430-2.4230). Age-of-menarche and age-of-pubarche were not different among participants in different biomarker or questionnaire quartiles. Conclusions: Results suggest that higher report of sunscreen use was associated with lower testosterone levels during thelarche and a non-linear relationship between age-of-thelarche and BP-3 biomarker. Results using questionnaire and biomarker to represent exposure are not completely consistent with each other, thus conclusions should be interpreted with caution.

Heat shock protein family A member 4-like (HSPA4L) has been shown to be overexpressed in osteoarthritis (OA) patients, but its role in OA process still unknown. Chondrocytes were stimulated with interleukin-1β (IL-1β) to mimic OA cell model in vitro, and rat was injected with monosodium iodoacetate (MIA) to construct OA rat model in vivo. The expression of HSPA4L, methyltransferase-like 3 (METTL3) and extracellular matrix (ECM)-related markers was examined by qRT-PCR or western blot. Cell proliferation and apoptosis were determined by CCK8 assay, EdU assay, TUNEL staining and flow cytometry. The levels of TNF-α and ROS were determined to assess cell inflammation and oxidative stress. The interaction between HSPA4L and METTL3 was confirmed by MeRIP assay and dual-luciferase reporter assay. Saffron-O and fast green staining was performed to evaluate cartilage degeneration in rats. HSPA4L expression was higher in OA patients and IL-1β-induced chondrocytes. Silencing of HSPA4L enhanced proliferation, while suppressed IL-1β-induced chondrocyte apoptosis, ECM degradation, inflammation and oxidative stress. METTL3 was upregulated in OA patients and IL-1β-induced chondrocytes, and it could increase HSPA4L expression by m6A modification. METTL3 knockdown inhibited IL-1β-induced chondrocyte injury, as well as alleviated cartilage degeneration in OA rat models, while these effects were reversed by HSPA4L overexpression. METTL3-mediated HSPA4L accelerated OA progression through m6A modification, providing a novel insight for OA treatment.

BackgroundDue to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression.MethodsWe screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus.ResultsMiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice.ConclusionsMiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.

Ferritin heavy chain 1, which FTH codes, is an important subunit of ferro-storing proteins and is indispensable in iron metabolism. It has been extensively researched in numerous organs and illnesses. Nevertheless, the relationship between FTH1 and osteoarthritis (OA) remains unclear. Here, we highlighted the significance of FTH1 in the pathophysiology of OA and identified it as a critical mediator of chondrocyte senescence and extracellular matrix(ECM) degradation. We discovered that FTH1 expression was downregulated in OA patients as well as mice after destabilized medial meniscus surgery (DMM). Knocking down of FTH1 caused articular cartilage damage and extracellular matrix degradation in cartilage explants. Furthermore, increased FTH1 expression can lessen the susceptibility of chondrocytes to ferroptosis, and reversed the decreased of SOX9 and aggrecan after DMM surgery in mice. The further study demonstrated that FTH1 relieved osteoarthritis by inhibiting the MAPK pathway in chondrocytes. Our study proved that FTH1 played an essential role in extracellular matrix degradation, ferroptosis and chondrocytes senescence during OA procedure, and intra-injection of adenovirus expressing FTH1 perhaps a viable and potential strategy for OA prevention and therapy.

Prenatal exposure to low doses of benzophenone-3 elicits disruption of cortical vasculature in fetuses through perturbations in Wnt/β-catenin signaling correlating with depression-like behavior in offspring mice

Effect of the UV-filter benzophenone-3 on intra-colonial social behaviors of the false clown anemonefish (Amphiprion ocellaris)

Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and cartilage degradation. Dendrobine (DEN) is reported to inhibit inflammation and oxidative stress in some diseases, but its role in chondrocyte senescence and OA progress has not yet been elucidated. Our study aimed to explore the protective effects of DEN on OA both in vitro and in vivo. We found that DEN inhibited extracellular matrix (ECM) degradation and promoted ECM synthesis. Meanwhile, DEN inhibited senescence-associated secretory phenotype (SASP) factors expression and senescence phenotype in IL-1β-treated chondrocytes. Furthermore, DEN improved mitochondrial function and reduced the production of intracellular reactive oxygen species (ROS). Also, DEN suppressed IL-1β-induced activation of the NF-κB pathway. Further, using NAC (ROS inhibitor), we found that DEN might inhibit NF-κB cascades by reducing ROS. Additionally, X-ray, micro-CT, and histological analyses in vivo demonstrated that DEN significantly alleviated cartilage inflammation, ECM degradation, and subchondral alterations in OA progression. In conclusion, DEN inhibits SASP factors expression and senescence phenotype in chondrocytes and alleviated the progression of OA via the ROS/NF-κB axis, which provides innovative strategies for the treatment of OA.

Osteoarthritis (OA) is a common degenerative disease that leads to pain, disability, and reduced quality of life. Orientin exhibits considerable anti-inflammatory and antioxidative properties, but its role in chondrocyte senescence and OA progress has not yet been fully characterized. The aim of this study was to evaluate the protective effects of orientin on OA. The role of orientin in extracellular matrix (ECM) degradation, mitochondrial homeostasis, and chondrocyte senescence was investigated in vitro. Meanwhile, we used molecular docking, small molecular inhibitors, and RNA interference to screen and validate candidate proteins regulated by orientin. In an anterior cruciate ligament transection (ACLT) rat model, radiograph, micro-CT, and various histological examinations were applied to evaluate the therapeutic effects of orientin on OA. We found that orientin inhibited ECM degradation and senescence-associated secretory phenotype (SASP) factor expression in interleukin (IL)-1β-treated chondrocytes. Additionally, orientin reduced the level of reactive oxygen species (ROS) and improved mitochondrial homeostasis. Furthermore, orientin suppressed IL-1β-induced activation of the nuclear factor kappa B (NF-κB) signalling pathway. We also found that orientin bound to phosphoinositide 3-kinase (PI3K) and inhibited NF-κB cascades via the PI3K/AKT pathway. In vivo, we demonstrated that orientin improved cartilage wear and reduced synovial inflammation and osteophyte in an ACLT rat model. Orientin improves mitochondrial homeostasis, inhibits chondrocyte senescence, and alleviates OA progress via the PI3K/AKT/NF-κB axis, which suggests that orientin is a potential effective therapeutic agent for OA.

Benzophenone-3 induced abnormal development of enteric nervous system in zebrafish through MAPK/ERK signaling pathway

Long-term effects of embryonic exposure to benzophenone-3 on neurotoxicity and behavior of adult zebrafish

Endocrine-disrupting chemicals such as benzophenone-3 (BP-3) can have severe consequences for human reproduction by affecting critical processes during pregnancy. To shed further light on potential harmful BP-3 actions, our current study addressed the impact of BP-3 on decidualization and trophoblast invasion. Decidualization was initiated in human endometrial stromal cells (THESC) upon treatment with a mixture of cAMP, progesterone, and estradiol. In parallel to hormonal treatment, the cells were exposed to different BP-3 concentrations ranging from 0.001 µM to 10 µM. The expression of decidualization and invasion markers was determined. Moreover, trophoblastic spheroids derived from JEG-3 cells were transferred to decidualized THESC after BP-3 exposure, and spheroid attachment and invasion were analyzed. Hormonal treatment successfully initiated decidualization in THESC, which was confirmed by increased prolactin levels and IGFBP1 and NCOA-3 mRNA expression. Notably, BP-3 exposure did not affect these markers. Furthermore, BP-3 changed neither THESC proliferation nor viability nor the frequency of cells expressing MMP2/9 or TIMP1/3. Trophoblastic spheroid attachment and outgrowth into THESC were not altered through any of the BP-3 concentrations applied. Our results do not provide evidence for an influence of BP-3 on the decidualization process and the capability of trophoblast cells to adhere and invade into endometrial stromal cells.

Osteoarthritis (OA) is the most common joint disease that causes pain and disability in the adult population. OA is primarily caused by trauma induced by an external force or by age-related cartilage damage. Chondrocyte hypertrophy or chondrocyte senescence is thought to play a role in the initiation and progression of OA. Although chondrocyte hypertrophy and cell death are both crucial steps during the natural process of endochondral bone formation, the abnormal activation of these two processes after injury or during aging seems to accelerate the progression of OA. However, the exact mechanisms of OA progression and these two processes remain poorly understood. Chondrocyte senescence and hypertrophy during OA share various markers and processes. In this study, we reviewed the changes that occur during chondrocyte hypertrophy or senescence in OA and the attempts that were made to regulate them. Regulation of hypertrophic or senescent chondrocytes might be a potential therapeutic target to slow down or stop OA progression; thus, a better understanding of the processes is required for management.