Faculty Opinions recommendation of Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees.

Abstract Background: Cartilage destruction caused by inflammation is a clinical challenge. Many studies have investigated cartilage destruction in adults, but little research was conducted on children. Results: The gaps without chondrocytes and ECM between the proliferative and hypertrophy zones of the GP cartilage were formation after the treatment of LPS, but the gaps were not observed in the AuNPs + LPS group. This finding can be attributed to the capability of AuNPs to target to the chondrocytes and reduce the release of inflammatory cytokines and secretion of ECM degradation factors induced by LPS. And then, the LPS-induced apoptosis rate of mouse chondrocytes and ECM degradation rate were inhibited. Finally, the balance of catabolic and anabolic factors in the ECM was maintained.Conclusion: These findings indicate that AuNPs can partially protect the cartilage of children from inflammatory damage by suppressing chondrocyte apoptosis and ECM degradation.

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Baicalein Alleviates Osteoarthritis Progression in Mice by Protecting Subchondral Bone and Suppressing Chondrocyte Apoptosis Based on Network Pharmacology

Frontiers in Pharmacology ◽

10.3389/fphar.2021.788392 ◽

2022 ◽

Vol 12 ◽

Author(s):

Nanxing Yi ◽

Yilin Mi ◽

Xiaotong Xu ◽

Naping Li ◽

Fan Zeng ◽

...

Keyword(s):

Molecular Docking ◽

Articular Cartilage ◽

Signaling Pathway ◽

Subchondral Bone ◽

Caspase 3 ◽

Synovial Inflammation ◽

Joint Disease ◽

Network Pharmacology ◽

Chondrocyte Apoptosis ◽

Apoptotic Signaling

As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.

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Galectin 3 Deficiency Alters Chondrocyte Primary Cilium Formation and Exacerbates Cartilage Destruction via Mitochondrial Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms21041486 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1486 ◽

Cited By ~ 2

Author(s):

Narjès Hafsia ◽

Marine Forien ◽

Félix Renaudin ◽

Delphine Delacour ◽

Pascal Reboul ◽

...

Keyword(s):

Primary Cilium ◽

Primary Cilia ◽

Mitochondrial Pathway ◽

Cartilage Destruction ◽

Terminal Deoxynucleotidyl Transferase ◽

Chondrocyte Apoptosis ◽

Cytochrome C Release ◽

Cilium Formation ◽

Galectin 3

Mechanical overload and aging are the main risk factors of osteoarthritis (OA). Galectin 3 (GAL3) is important in the formation of primary cilia, organelles that are able to sense mechanical stress. The objectives were to evaluate the role of GAL3 in chondrocyte primary cilium formation and in OA in mice. Chondrocyte primary cilium was detected in vitro by confocal microscopy. OA was induced by aging and partial meniscectomy of wild-type (WT) and Gal3-null 129SvEV mice (Gal3−/−). Primary chondrocytes were isolated from joints of new-born mice. Chondrocyte apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase 3 activity and cytochrome c release. Gene expression was assessed by qRT-PCR. GAL3 was localized at the basal body of the chondrocyte primary cilium. Primary cilia of Gal3−/− chondrocytes were frequently abnormal and misshapen. Deletion of Gal3 triggered premature OA during aging and exacerbated joint instability-induced OA. In both aging and surgery-induced OA cartilage, levels of chondrocyte catabolism and hypertrophy markers and apoptosis were more severe in Gal3−/− than WT samples. In vitro, Gal3 knockout favored chondrocyte apoptosis via the mitochondrial pathway. GAL3 is a key regulator of cartilage homeostasis and chondrocyte primary cilium formation in mice. Gal3 deletion promotes OA development.

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Less mechanical loading attenuates osteoarthritis by reducing cartilage degeneration, subchondral bone remodelling, secondary inflammation, and activation of NLRP3 inflammasome

Bone and Joint Research ◽

10.1302/2046-3758.910.bjr-2019-0368.r2 ◽

2020 ◽

Vol 9 (10) ◽

pp. 731-741

Author(s):

Zhennian He ◽

Pengfei Nie ◽

Jianli Lu ◽

Yong Ling ◽

Jian Guo ◽

...

Keyword(s):

Mechanical Loading ◽

Inflammatory Cytokines ◽

Subchondral Bone ◽

Cartilage Damage ◽

Cartilage Destruction ◽

Enzyme Linked Immunosorbent Assay ◽

Tartrate Resistant Acid Phosphatase ◽

Tail Suspension ◽

Mineral Density ◽

Bone Changes

Aims Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA. Methods A post-traumatic OA model was established in 20 rats (12 weeks old, male). Ten rats were treated with less mechanical loading through intermittent tail suspension, while another ten rats were treated with normal mechanical loading. Cartilage damage was determined by gross appearance, Safranin O/Fast Green staining, and immunohistochemistry examinations. Subchondral bone changes were analyzed by micro-CT and tartrate-resistant acid phosphatase (TRAP) staining, and serum inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). Results Our radiographs showed that joint space was significantly enlarged in rats with less mechanical loading. Moreover, cartilage destruction was attenuated in the less mechanical loading group with lower histological damage scores, and lower expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, matrix metalloproteinase (MMP)-3, and MMP-13. In addition, subchondral bone abnormal changes were ameliorated in OA rats with less mechanical loading, as reduced bone mineral density (BMD), bone volume/tissue volume (BV/TV), and number of osteophytes and osteoclasts in the subchondral bone were observed. Finally, the level of serum inflammatory cytokines was significantly downregulated in the less mechanical loading group compared with the normal mechanical loading group, as well as the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), caspase-1, and interleukin 1β (IL-1β) in the cartilage. Conclusion Less mechanical loading alleviates cartilage destruction, subchondral bone changes, and secondary inflammation in OA joints. This study provides fundamental insights into the benefit of non-weight loading rest for patients with OA. Cite this article: Bone Joint Res 2020;9(10):731–741.

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Subchondral bone microenvironment in osteoarthritis and pain

Bone Research ◽

10.1038/s41413-021-00147-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Yan Hu ◽

Xiao Chen ◽

Sicheng Wang ◽

Yingying Jing ◽

Jiacan Su

Keyword(s):

Subchondral Bone ◽

Therapeutic Potential ◽

Critical Role ◽

Sensory Nerve ◽

Cartilage Degeneration ◽

Cartilage Destruction ◽

Future Research ◽

Bone Lesions ◽

Obesity Trends

AbstractOsteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.

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Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208406 ◽

2016 ◽

Vol 75 (11) ◽

pp. 2045-2052 ◽

Cited By ~ 22

Author(s):

Yoonkyung Won ◽

Youngnim Shin ◽

Churl-Hong Chun ◽

Yongsik Cho ◽

Chul-Won Ha ◽

...

Keyword(s):

Molecular Mechanisms ◽

Expression Profiles ◽

Hypoxia Inducible Factor ◽

Gene Expression Profiles ◽

Cartilage Destruction ◽

Terminal Deoxynucleotidyl Transferase ◽

Chondrocyte Apoptosis ◽

Double Knockout ◽

Nicotinamide Phosphoribosyltransferase ◽

Human And Mouse

ObjectiveThe zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.MethodsExperimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).ResultsMTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.ConclusionsMTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.

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