Low-intensity pulsed ultrasound delays the progression of osteoarthritis by regulating the YAP-RIPK1-NF-κB axis and influencing autophagy.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation of the joint. As the disease progresses, patients will gradually develop symptoms such as pain, physical limitations and even disability. The risk factors for OA include genetics, gender, trauma, obesity, and age. Unfortunately, due to limited understanding of its pathological mechanism, there are currently no effective drugs or treatments to suspend the progression of osteoarthritis. In recent years, some studies found that low-intensity pulsed ultrasound (LIPUS) may have a positive effect on osteoarthritis. Nonetheless, the exact mechanism by which LIPUS affects osteoarthritis remains unknown. It is valuable to explore the specific mechanism of LIPUS in the treatment of OA. METHODS: In this study, we validated the potential therapeutic effect of LIPUS on osteoarthritis by regulating the YAP-RIPK1-NF-κB axis at both cellular and animal levels. To verify the effect of YAP on OA, the expression of YAP was knocked down or overexpressed by siRNA and plasmid in chondrocytes and adeno-associated virus was injected into the knee joint of rats. The effect of LIPUS was investigated in inflammation chondrocytes induced by IL-1ß and in the post-traumatic OA model. RESULTS: In this study, we observed that YAP plays an important role in the development of osteoarthritis and knocking down of YAP significantly inhibited the inflammation and alleviated cartilage degeneration. We also demonstrated that the expression of YAP was increased in osteoarthritis chondrocytes and YAP could interact with RIPK1, thereby regulating the NF-κB signal pathway and influencing inflammation. Moreover, we also discovered that LIPUS decreased the expression of YAP by restoring the impaired autophagy capacity and inhibiting the binding between YAP and RIPK1, thereby delaying the progression of osteoarthritis. Animal experiment showed that LIPUS could inhibit cartilage degeneration and alleviate the progression of OA. CONCLUSIONS: These results showed that LIPUS is effective in inhibiting inflammation and cartilage degeneration and alleviate the progression of OA. As a result, our results provide new insight of mechanism by which LIPUS delays the development of osteoarthritis, offering a novel therapeutic regimen for osteoarthritis.

Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway.

Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1ß (IL-1ß) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1ß and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1ß and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA.

DMT1-mediated iron overload accelerates cartilage degeneration in Hemophilic Arthropathy through the mtDNA-cGAS-STING axis.

INTRODUCTION: Excess iron contributes to Hemophilic Arthropathy (HA) development. Divalent metal transporter 1 (DMT1) delivers iron into the cytoplasm, thus regulating iron homeostasis. OBJECTIVES: We aimed to investigate whether DMT1-mediated iron homeostasis is involved in bleeding-induced cartilage degeneration and the molecular mechanisms underlying iron overload-induced chondrocyte damage. METHODS: This study established an in vivo HA model by puncturing knee joints of coagulation factor VIII gene knockout mice with a needle, and mimicked iron overload conditions in vitro by treatment of Ferric ammonium citrate (FAC). RESULTS: We demonstrated that blood exposure caused iron overload and cartilage degeneration, as well as elevated expression of DMT1. Furthermore, DMT1 silencing alleviated blood-induced iron overload and cartilage degeneration. In hemophilic mice, articular cartilage degeneration was also suppressed by intro-articularly injection of DMT1 adeno-associated virus 9 (AAV9). Mechanistically, RNA-sequencing analysis indicated the association between iron overload and cGAS-STING pathway. Further, iron overload triggered mtDNA-cGAS-STING pathway activation, which could be effectively mitigated by DMT1 silencing. Additionally, we discovered that RU.521, a potent Cyclic GMP-AMP Synthase (cGAS) inhibitor, successfully suppressed the downward cascades of cGAS-STING, thereby protecting against chondrocyte damage. CONCLUSION: Taken together, DMT1-mediated iron overload promotes chondrocyte damage and murine HA development, and targeted DMT1 may provide therapeutic and preventive approaches in HA.

Erratum: Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

[This corrects the article DOI: 10.1016/j.isci.2023.107647.].

P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability.

Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes. First, we demonstrated that high P21 expression was observed in the cartilage from OA patients and destabilized medial meniscus (DMM) mice, and in osteoarthritic chondrocytes induced by IL-1ß, FAC and erastin. P21 knockdown exacerbated the reduction of Col2a1 and promoted the upregulation of MMP13 in osteoarthritic chondrocytes. Meanwhile, P21 knockdown exacerbated cartilage degradation in DMM-induced OA mouse models and decreased GPX4 expression in vivo. Furthermore, P21 knockdown sensitized chondrocytes to ferroptosis induced by erastin, which was closely associated with the accumulation of lipid peroxides. In mechanism, we demonstrated that P21 regulated the stability of GPX4 protein, and the regulation was independent of NRF2. Meanwhile, we found that P21 significantly affected the recruitment of GPX4 to linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. Overall, our results suggest that P21 plays an essential anti-ferroptosis role in OA by regulating the stability of GPX4.

Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

Osteoarthritis (OA) is a prevalent degenerative disease of the elderly. The NRF2 antioxidant system plays a critical role in maintaining redox balance. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant. This research aimed to determine whether MitoQ alleviated OA and the role of the NRF2/Parkin axis in MitoQ-mediated protective effects. In interleukin (IL)-1ß-induced OA chondrocytes, MitoQ activated the NRF2 pathway, reducing extracellular matrix (ECM) degradation and inflammation. MitoQ also increased glutathione peroxidase 4 (GPX4) expression, leading to decreased levels of reactive oxygen species (ROS) and lipid ROS. Silencing NRF2 weakened MitoQ's protective effects, while knockdown of Parkin upregulated the NRF2 pathway, inhibiting OA progression. Intra-articular injection of MitoQ mitigated cartilage destruction in destabilized medial meniscus (DMM)-induced OA mice. Our study demonstrates that MitoQ maintains cartilage homeostasis in vivo and in vitro through the NRF2/Parkin axis. We supplemented the negative feedback regulation mechanism between NRF2 and Parkin. These findings highlight the therapeutic potential of MitoQ for OA treatment.

Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis.

Osteoarthritis (OA) is a multifactorial and increasingly prevalent degenerative disease that affects the whole joint. The pathogenesis of OA is poorly understood and there is a lack of therapeutic interventions to reverse the pathological process of this disease. Accumulating studies have shown that the overproduction of reactive oxygen species (ROS) and ROS-induced lipid peroxidation are involved in the pathogenesis of OA. 4-Hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) have received considerable attention for their role in cartilage degeneration and subchondral bone remodeling during OA development. Ferroptosis is a form of cell death characterized by a lack of control of membrane lipid peroxidation and recent studies have suggested that chondrocyte ferroptosis contributes to OA progression. In this review, we aim to discuss lipid peroxidation-derived 4-HNE and MDA in the progression of OA. In addition, the therapeutic potential for OA by controlling the accumulation of lipid peroxidation and inhibiting chondrocyte ferroptosis are discussed.

The roles of the Hippo-YAP signalling pathway in Cartilage and Osteoarthritis.

Osteoarthritis (OA) is an age-related disease, characterized by cartilage degeneration. The pathogenesis of OA is complicated and the current therapeutic approaches for OA are limited. Cartilage, an integral part of the skeletal system composed of chondrocytes, is essential for skeletal development, tissue patterning, and maintaining the normal activity of joints. The development, homeostasis and degeneration of cartilage are tightly associated with OA. Over the past decade, accumulating evidence indicates that Hippo/YAP is a vital biochemical signalling pathway that strictly governs tissue development and homeostasis. The joint tissues, especially for cartilage, are sensitive to changes of Hippo/YAP signalling. In this review, we summarize the role of Hippo/YAP signalling in cartilage and discuss its involvement in OA progression from points of cartilage degradation, subchondral bone remodeling, and synovial alteration. We also highlight the potential therapeutic implications of Hippo/YAP signalling and further discuss current limitations and controversy on Hippo/YAP-based application for OA treatment.

Corrigendum: Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway.

[This corrects the article DOI: 10.3389/fphar.2022.791376.].

JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.

Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1ß-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.

Inhibition of TRADD ameliorates chondrocyte necroptosis and osteoarthritis by blocking RIPK1-TAK1 pathway and restoring autophagy.

Osteoarthritis (OA) is an age-related disease characterized by cartilage degeneration. TNFR1-associated death domain protein (TRADD) is a key upstream molecule of TNF-α signals but its role in OA pathogenesis is unknown. This study aimed to verify that whether inhibition of TRADD could protect against chondrocyte necroptosis and OA, and further elucidate the underlying mechanism. We demonstrated that TNF-α-related OA-like phenotypes including inflammation response, extracellular matrix degradation, apoptosis, and necroptosis in chondrocytes were inhibited by TRADD deficiency. Furthermore, TRADD interacted with TRAF2 and knockdown of TRADD suppressed the activation of RIPK1-TAK1-NF-κB signals and restored impaired autophagy. ICCB-19, the selective inhibitor of TRADD, also attenuated necroptosis in chondrocytes. Mechanismly, ICCB-19 blocked the phosphorylation of TAK1-NF-κB signals and restored impaired autophagy, whereas inhibiting autophagic process with 3-Methyladenine compromised these effects of ICCB-19. The in vivo study showed that the intra-articular injection of ICCB-19 rescued the expression of collagen alpha-1(II) chain and LC3, and mitigated the cartilage degeneration of OA mice. This study demonstrates that TRADD mediates TNF-α-induced necroptosis and OA-like phenotypes of chondrocytes and suggests that ICCB-19 suppresses chondrocyte damage and cartilage degeneration by inhibiting TNF-α-TRADD-mediated signals and dysregulation of autophagy in chondrocytes. ICCB-19 may serve as an important option for OA therapy.

Contribution of preoperative gut microbiota in postoperative neurocognitive dysfunction in elderly patients undergoing orthopedic surgery.

Objective: To investigate the role of gut microbiota and metabolites in POCD in elderly orthopedic patients, and screen the preoperative diagnostic indicators of gut microbiota in elderly POCD. Method: 40 elderly patients undergoing orthopedic surgery were enrolled and divided into Control group and POCD group following neuropsychological assessments. Gut microbiota was determined by 16S rRNA MiSeq sequencing, and metabolomics of GC-MS and LC-MS was used to screen the differential metabolites. We then analyzed the pathways enriched by metabolites. Result: There was no difference in alpha or beta diversity between Control group and POCD group. There were significant differences in 39 ASV and 20 genera bacterium in the relative abundance. Significant diagnostic efficiency analyzed by the ROC curves were found in 6 genera bacterium. Differential metabolites in the two groups including acetic acid, arachidic acid, pyrophosphate etc. were screened out and enriched to certain metabolic pathways which impacted the cognition function profoundly. Conclusion: Gut microbiota disorders exist preoperatively in the elderly POCD patients, by which there could be a chance to predict the susceptible population. Clinical Trial Registration: [http://www.chictr.org.cn/edit.aspx?pid=133843&htm=4], identifier [ChiCTR2100051162].

Physalin A alleviates intervertebral disc degeneration via anti-inflammatory and anti-fibrotic effects.

Background: The incidence of intervertebral disc degeneration (IVDD) is a common degenerative disease with inflammation, decreased autophagy, and progression of fibrosis as its possible pathogenesis. Physalin A (PA) is a widely studied anti-inflammatory drug. However, its therapeutic effects on IVDD remain unexplored. Therefore, we aimed to explore the therapeutic potential of PA in IVDD progression. Materials and methods: In vivo, we investigated PA bioactivity using a puncture-induced IVDD rat model. IVDD signals and height changes were detected using X-ray, micro-CT, and MRI, and structural and molecular lesions using histological staining and immunohistochemistry of intervertebral disc sections. In vivo, interleukin-1 beta (IL-1ß) and TGF-ß1 were employed to establish inflammation fibrotic nucleus pulposus (NP) cells. The PA effect duration, concentration, influence pathways, and pathological changes in IVDD treatment were elucidated using western blotting, real-time PCR, and immunofluorescence. Results: PA exerted significant effects on IVDD remission due to anti-inflammation, fibrosis reduction, and autophagy enhancement. In vitro, PA improved inflammation by blocking the NF-κB and MAPK pathways, whereas it promoted autophagy via the PI3K/AKT/mTOR pathway and affected fibrotic progression by regulating the SMAD2/3 pathway. Moreover, PA improved the disc degeneration process in IVDD model. Conclusions: PA exhibited significant anti-inflammatory and anti-fibrotic effects and improved autophagy in vivo and in vitro IVDD models, thus effectively relieving IVDD progression, indicating it is a promising agent for IVDD treatment. The translational potential of this article: This study successfully reveals that PA, a natural bioactive withanolide, effectively relieved IVDD progression via inflammation inhibition, fibrosis reduction, and autophagy enhancement, indicating it is a promising agent for IVDD treatment.

Mulberroside A alleviates osteoarthritis via restoring impaired autophagy and suppressing MAPK/NF-κB/PI3K-AKT-mTOR signaling pathways.

Osteoarthritis (OA) is a trauma-/age-related degenerative disease characterized by chronic inflammation as one of its pathogenic mechanisms. Mulberroside A (MA), a natural bioactive withanolide, demonstrates anti-inflammatory properties in various diseases; however, little is known about the effect of MA on OA. We aim to examine the role of MA on OA and to identify the potential mechanisms through which it protects articular cartilage. In vitro, MA improved inflammatory response, anabolism, and catabolism in IL-1ß-induced OA chondrocytes. The chondroprotective effects of MA were attributed to suppressing the MAPK, NF-κB, and PI3K-AKT-mTOR signaling pathways, as well as promoting the autophagy process. In vivo, intra-articular injection of MA reduced the cartilage destruction and reversed the change of anabolic and catabolic-related proteins in destabilized medial meniscus (DMM)-induced OA models. Thus, the study indicates that MA exhibits a chondroprotective effect and might be a promising agent for OA treatment.

Desferoxamine protects against hemophilic arthropathy through the upregulation of HIF-1α-BNIP3 mediated mitophagy.

AIMS: Hemophilic arthropathy (HA) is a typically iron overload induced joint disease secondary to continuous joint bleeding, however, the exact role of iron chelators in HA has not been fully elucidated. In the present study, we investigated whether desferoxamine (DFO), an iron chelator, could limit the development of HA and the underlying mechanisms. MATERIALS AND METHODS: A HA mice model was established by needle puncture in the left knees of FVIII-deficient hemophilic mice. HA progression was evaluated at 8 weeks after DFO administration. Moreover, chondrocytes were treated with ferric ammonium citrate (FAC) to mimic iron overload in vitro. Modulating effect of DFO on iron overload induced oxidative stress, chondrocytes apoptosis and extracellular matrix (ECM) degradation and the role of HIF-1α-BNIP3 mediated mitophagy were examined. KEY FINDINGS: We found that DFO limited the development of HA and protected iron overload induced ECM degradation, chondrocytes apoptosis and oxidative stress. Besides chelating Fe2+, we found that HIF-1α-BNIP3 mediated mitophagy played important roles in the protective effect of DFO. HIF-1α inhibition suppressed chondrocytes mitophagy process and partly diminished the protective effect of DFO on chondrocytes iron overload. SIGNIFICANCE: In conclusion, DFO could protect against HA development via HIF-1α-BNIP3 mediated mitophagy, suggesting DFO might be a potential therapeutic supplement for HA treatment.

Indirubin protects chondrocytes and alleviates OA by inhibiting the MAPK and NF-κB pathways.

PHARMACOLOGICAL RELEVANCE: Indirubin (IR) is a key active ingredient in the traditional Chinese medication QingDai, also called indigo naturalis, which are extensively used in China to treat chronic diseases, such as inflammation and cancer. However, the function of IR in reducing chondrocyte inflammation in osteoarthritis (OA) is still unclear. AIM OF THE STUDY: The aim of this research was to examine how IR inhibits arthritis and to highlight some of its cellular-level processes. MATERIALS AND METHODS: Chondrocytes from the knee joint of C57 mice were gathered and grown for in vitro tests and used to determine the toxicity of IR toward chondrocytes using a CCK8 kit. Chondrocytes were treated with IL-1ß and IR or with IL-1ß alone, and western blotting was used to determine the expression levels of inflammatory mediators. Meanwhile, through the identification and examination of pertinent markers via quantitative PCR. By using PCR assays, western blotting, toluidine blue staining and safranin O staining, the expression of proteoglycan (AGG) and type II collagen (collagen II) was investigated. Furthermore, western blotting was used to detect activation of the NF-κB and MAPK signaling pathways, and immunofluorescence was used to detect p65 nuclear translocation. In an in vivo experiment, C57BL/6 mice were subjected to destabilization of the medial meniscus (DMM) surgery to produce an OA model, and IR was injected into the articular cavity for 8 weeks. Eventually, the mice were killed, and samples of the knee joints were obtained for histological examination and analysis. RESULTS: IR significantly reduced the expression of inflammatory regulators in chondrocytes treated with IL-1ß, including iNOS and COX-2. Inhibition of IL-1ß induced production of the key catabolic enzymes MMP3, MMP13 and A5. Additionally, an improvement in the downregulation of collagen II and AGG expression was observed. Moreover, IR prevented the aberrant IL-1ß-induced activation of the NF-κB and MAPK signaling pathways, which resulted in downregulation of p65 and p38 expression. Compared to the DMM group, the severity of cartilage injury in animals was dramatically lessened and OARSI scores were lower in the treated groups. CONCLUSION: According to the above findings, IR is quite effective in preventing arthritis both in vivo and in vitro, suggesting that IR may be employed as a possible anti-arthritis drug.

Oroxin B alleviates osteoarthritis through anti-inflammation and inhibition of PI3K/AKT/mTOR signaling pathway and enhancement of autophagy.

Background: Osteoarthritis (OA) is a common aging-related degenerative joint disease with chronic inflammation as its possible pathogenesis. Oroxin B (OB), a flavonoid isolated from traditional Chinese herbal medicine, possesses anti-inflammation properties which may be involved in regulating the pathogenesis of OA, but its mechanism has not been elucidated. Our study was the first to explore the potential chondroprotective effect and elucidate the underlying mechanism of OB in OA. Methods: In vitro, primary mice chondrocytes were stimulated with IL-1ß along with or without the administration of OB or autophagy inhibitor 3-methyladenine (3-MA). Cell viability assay was measured with a cell counting kit-8 (CCK-8). The phenotypes of anabolic-related (Aggrecan and Collagen II), catabolic-related (MMP3, MMP13, and ADAMTS5), inflammation-related (iNOS, COX-2, TNF-α, IL-6, and IL-1ß), and markers of related signaling pathways in chondrocytes with different treatment were detected through western blot, RT-qPCR, and immunofluorescent staining. In vivo, the destabilized medial meniscus (DMM) operation was performed to establish the OA mice model. After knee intra-articular injection with OB for 8 weeks, the mice's knee joints were obtained for subsequent histological staining and analysis. Results: OB reversed the expression level of anabolic-related proteins (Aggrecan and Collagen II) and catabolic-related (MMP3, MMP13, and ADAMTS5) in IL-1ß-induced chondrocytes. Mechanistically, OB suppressed the inflammatory response stimulated by IL-1ß, as the inflammation-related (iNOS, COX-2, TNF-α, IL-6, and IL-1ß) markers were downregulated after the administration of OB in IL-1ß-induced chondrocytes. Besides, the activation of PI3K/AKT/mTOR signaling pathway induced by IL-1ß could be inhibited by OB. Additionally, the autophagy process impaired by IL-1ß could be rescued by OB. What's more, the introduction of 3-MA to specifically inhibit the autophagic process impairs the protective effect of OB on cartilage. In vivo, histological staining revealed that intra-articular injection of OB attenuated the cartilage degradation, as well as reversed the expression level of anabolic and catabolic-related proteins such as Aggrecan, Collagen II, and MMP13 induced in DMM-induced OA models. Conclusions: The study verified that OB exhibited the chondroprotective effect by anti-inflammatory, inhibiting the PI3K/AKT/mTOR signaling pathway, and enhancing the autophagy process, indicating that OB might be a promising agent for the treatment of OA.

Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.

Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.

Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway.

Objective: Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to OA progression. Because iron deposition is a major pathological event in ferroptosis, deferoxamine (DFO), an effective iron chelator, has been used to inhibit ferroptosis in various degenerative disease models. Nevertheless, its OA treatment efficacy remains unknown. We aimed to determine whether DFO alleviates chondrocyte ferroptosis and its effect on OA and to explore its possible mechanism. Methods: Interleukin-1ß (IL-1ß) was used to simulate inflammation, and chondrocyte ferroptosis was induced by erastin, a classic ferroptosis inducer. A surgical destabilized medial meniscus mouse model was also applied to simulate OA in vivo, and erastin was injected into the articular cavity to induce mouse knee chondrocyte ferroptosis. We determined the effects of DFO on ferroptosis and injury-related events: chondrocyte inflammation, extracellular matrix degradation, oxidative stress, and articular cartilage degradation. Results: IL-1ß increased the levels of ROS, lipid ROS, and the lipid peroxidation end product malondialdehyde (MDA) and altered ferroptosis-related protein expression in chondrocytes. Moreover, ferrostatin-1 (Fer-1), a classic ferroptosis inhibitor, rescued the IL-1ß-induced decrease in collagen type II (collagen II) expression and increase in matrix metalloproteinase 13 (MMP13) expression. Erastin promoted MMP13 expression in chondrocytes but inhibited collagen II expression. DFO alleviated IL-1ß- and erastin-induced cytotoxicity in chondrocytes, abrogated ROS and lipid ROS accumulation and the increase in MDA, improved OA-like changes in chondrocytes, and promoted nuclear factor E2-related factor 2 (Nrf2) antioxidant system activation. Finally, intra-articular injection of DFO enhanced collagen II expression in OA model mice, inhibited erastin-induced articular chondrocyte death, and delayed articular cartilage degradation and OA progression. Conclusion: Our research confirms that ferroptosis occurs in chondrocytes under inflammatory conditions, and inhibition of chondrocyte ferroptosis can alleviate chondrocyte destruction. Erastin-induced chondrocyte ferroptosis can stimulate increased MMP13 expression and decreased collagen II expression in chondrocytes. DFO can suppress chondrocyte ferroptosis and promote activation of the Nrf2 antioxidant system, which is essential for protecting chondrocytes. In addition, ferroptosis inhibition by DFO injection into the articular cavity may be a new OA treatment.

Prognostic value of CDCA3 in kidney renal papillary cell carcinoma.

Kidney renal papillary cell carcinoma (KIRP) is a type of low-grade malignant renal cell carcinoma. Huge challenges remain in the treatment of KIRP. Cell division cycle associated 3 (CDCA3) participates in human physiological and pathological processes. However, its role in KIRP has not been established. Here, we evaluated the prognostic value of CDCA3 in KIRP using a comprehensive bioinformatics approach. Data for CDCA3 expression in KIRP were obtained from online database. Different expression genes between high and low CDCA3 expression groups were identified and evaluated by performing Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A gene set enrichment analysis was performed to elucidate the function and pathway differences between the different. Differences in immune cell infiltration between low and high CDCA3 expression groups were analyzed by a single-sample GSEA method for immune cells. A protein-protein interaction network was generated and hub genes were identified. UALCAN was used to analyze associations between the mRNA expression levels of CDCA3 in KIRP tissues with clinicopathologic parameters. The diagnostic efficacy of CDCA3 for KIRP was analyzed by ROC analysis. Logistic regression was used to analyze relationships between the clinicopathological characteristics and CDCA3 expression. Our results indicated that high CDCA3 mRNA expression is significantly associated with some clinicopathologic parameters in KIRP patients High CDCA3 mRNA expression associated with a shorter overall survival, progression-free interval, and disease-special survival. Taken together, CDCA3 is a potential target for the development of anti-KIRP therapeutics and is an efficient prognostic marker.