scholarly journals Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovanna Nalesso ◽  
Anne-Sophie Thorup ◽  
Suzanne Elizabeth Eldridge ◽  
Anna De Palma ◽  
Amanpreet Kaur ◽  
...  
Keyword(s):  
Medial Meniscus ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Cartilage Damage ◽  
Regenerative Processes ◽  
Cartilage Homeostasis ◽  
Calmodulin Kinase ◽  
Wnt Ligands ◽  
Pharmacological Blockade

AbstractWNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been associated with the onset of different diseases. Here we investigated the role of the WNT/Calcium Calmodulin Kinase II (CaMKII) pathway in osteoarthritis. We identified Heme Oxygenase I (HMOX1) and Sox-9 as specific markers of the WNT/CaMKII signalling in articular chondrocytes through a microarray analysis. We showed that the expression of the activated form of CaMKII, phospho-CaMKII, was increased in human and murine osteoarthritis and the expression of HMOX1 was accordingly reduced, demonstrating the activation of the pathway during disease progression. To elucidate its function, we administered the CaMKII inhibitor KN93 to mice in which osteoarthritis was induced by resection of the anterior horn of the medial meniscus and of the medial collateral ligament in the knee joint. Pharmacological blockade of CaMKII exacerbated cartilage damage and bone remodelling. Finally, we showed that CaMKII inhibition in articular chondrocytes upregulated the expression of matrix remodelling enzymes alone and in combination with Interleukin 1. These results suggest an important homeostatic role of the WNT/CaMKII signalling in osteoarthritis which could be exploited in the future for therapeutic purposes.

Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway

Rheumatology ◽  
2021 ◽  
Author(s):  
Liangliang Liu ◽  
Chang Zhao ◽  
Haiyan Zhang ◽  
Yuheng Lu ◽  
Bingsheng Luo ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Medial Meniscus ◽  
Articular Chondrocytes ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Osteoarthritis Progression ◽  
Osteoarthritis Research Society ◽  
Tgf Β1

Abstract Objectives This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in osteoarthritis (OA) pathology. Methods Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated β-galactosidase (SA-βGal) staining, γH2AX, p21, and p16INK4a were analyzed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-β1/Smad2 signaling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. Results Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-β1/Smad2 signaling in chondrocytes. Conclusions Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-β1/Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p/asporin/Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.

scholarly journals TGFβ/BMP Signaling Pathway in Cartilage Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 969 ◽  
Author(s):  
Nathalie Thielen ◽  
Peter van der Kraan ◽  
Arjan van Caam
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Cartilage Homeostasis ◽  
Cartilage Biology ◽  
Matrix Production

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis

2001 ◽  
Vol 101 (6) ◽  
pp. 593-599 ◽  
Author(s):  
Ilaria MAZZETTI ◽  
Brunella GRIGOLO ◽  
Lia PULSATELLI ◽  
Paolo DOLZANI ◽  
Tania SILVESTRI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Cartilage Damage ◽  
Organ Donors ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Oxygen Intermediates

Osteoarthritis and rheumatoid arthritis are characterized by focal loss of cartilage due to an up-regulation of catabolic pathways, induced mainly by pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor α (TNFα). Since reactive oxygen species are also involved in this extracellular-matrix-degrading activity, we aimed to compare the chondrocyte oxidative status responsible for cartilage damage occurring in primarily degenerative (osteoarthritis) and inflammatory (rheumatoid arthritis) joint diseases. Human articular chondrocytes were isolated from patients with osteoarthritis or rheumatoid arthritis, or from multi-organ donors, and stimulated with IL-1β and/or TNFα. We evaluated the oxidative stress related to reactive nitrogen and oxygen intermediates, measuring NO2- as a stable end-product of nitric oxide generation and superoxide dismutase as an antioxidant enzyme induced by radical oxygen species. We found that cells from patients with osteoarthritis produced higher levels of NO2- than those from patients with rheumatoid arthritis. In addition, IL-1β was more potent than TNFα in inducing nitric oxide in both arthritides, and TNFα alone was almost ineffective in cells from rheumatoid arthritis patients. We also observed that the intracellular content of copper/zinc superoxide dismutase (Cu/ZnSOD) was always lower in rheumatoid arthritis chondrocytes than in those from multi-organ donors, whereas no differences were found in intracellular manganese SOD (MnSOD) or in supernatant Cu/ZnSOD and MnSOD levels. Moreover, intracellular MnSOD was up-regulated by cytokines in osteoarthritis chondrocytes. In conclusion, our results suggest that nitric oxide may play a major role in altering chondrocyte functions in osteoarthritis, whereas the harmful effects of radical oxygen species are more evident in chondrocytes from patients with rheumatoid arthritis, due to an oxidant/antioxidant imbalance.

scholarly journals Expression of Angiotensin II Receptor-1 in Human Articular Chondrocytes

Arthritis ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Yuki Kawakami ◽  
Kosuke Matsuo ◽  
Minako Murata ◽  
Kazuo Yudoh ◽  
Hiroshi Nakamura ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Articular Chondrocytes ◽  
Cartilage Damage ◽  
Immunohistochemical Analysis ◽  
Human Articular Chondrocytes ◽  
Cartilage Tissue ◽  
Angiotensin Ii Receptors ◽  
Angiotensin Ii Receptor

Background. Besides its involvement in the cardiovascular system, the renin-angiotensin-aldosterone (RAS) system has also been suggested to play an important role in inflammation. To explore the role of this system in cartilage damage in arthritis, we investigated the expression of angiotensin II receptors in chondrocytes. Methods. Articular cartilage was obtained from patients with osteoarthritis, rheumatoid arthritis, and traumatic fractures who were undergoing arthroplasty. Chondrocytes were isolated and cultured in vitro with or without interleukin (IL-1). The expression of angiotensin II receptor types 1 (AT1R) and 2 (AT2R) mRNA by the chondrocytes was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). AT1R expression in cartilage tissue was analyzed using immunohistochemistry. The effect of IL-1 on AT1R/AT2R expression in the chondrocytes was analyzed by quantitative PCR and flow cytometry. Results. Chondrocytes from all patient types expressed AT1R/AT2R mRNA, though considerable variation was found between samples. Immunohistochemical analysis confirmed AT1R expression at the protein level. Stimulation with IL-1 enhanced the expression of AT1R/AT2R mRNA in OA and RA chondrocytes. Conclusions. Human articular chondrocytes, at least partially, express angiotensin II receptors, and IL-1 stimulation induced AT1R/AT2R mRNA expression significantly.

scholarly journals Pink1-Mediated Chondrocytic Mitophagy Contributes to Cartilage Degeneration in Osteoarthritis

2019 ◽  
Vol 8 (11) ◽  
pp. 1849 ◽  
Author(s):  
Hyo Jung Shin ◽  
Hyewon Park ◽  
Nara Shin ◽  
Hyeok Hee Kwon ◽  
Yuhua Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Articular Chondrocytes ◽  
Mitochondrial Fission ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Osteoarthritic Cartilage ◽  
Monosodium Iodoacetate ◽  
Biochemical Mechanisms ◽  
Related Proteins

Cartilage loss is a central event in the pathogenesis of osteoarthritis (OA), though other than mechanical loading, the biochemical mechanisms underlying OA pathology remain poorly elucidated. We investigated the role of Pink1-mediated mitophagy in mitochondrial fission, a crucial process in OA pathogenesis. We used a monosodium iodoacetate (MIA)-induced rodent model of OA, which inhibits the activity of articular chondrocytes, leading to disruption of glycolytic energy metabolism and eventual cell death. The OA rat cartilage exhibits significant induction of autophagy-related proteins LC3B and p62, similar to human osteoarthritic cartilage. Moreover, expression of Pink1 and Parkin proteins were also increased in OA. Here, we confirm that Pink1-mediated mitophagy leads to cell death in chondrocytes following MIA treatment, while deficiency in Pink1 expression was associated with decreased cartilage damage and pain behaviors in MIA-induced OA. Finally, we found that autophagy and mitophagy-related genes are highly expressed in human osteoarthritic cartilage. These results indicate that OA is a degenerative condition associated with mitophagy, and suggest that targeting the Pink1 pathway may provide a therapeutic avenue for OA treatment.

scholarly journals Lactoferrin Inhibits IL-1β-Induced Chondrocyte Apoptosis Through AKT1-Induced CREB1 Activation

2015 ◽  
Vol 36 (6) ◽  
pp. 2456-2465 ◽  
Author(s):  
Huaming Xue ◽  
Yihui Tu ◽  
Tong Ma ◽  
Xiaodong Liu ◽  
Tao Wen ◽  
...  
Keyword(s):  
Western Blotting ◽  
Molecular Mechanisms ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Inhibitory Effect ◽  
Chondrocyte Apoptosis ◽  
Flow Cytometric ◽  
Apoptotic Effect

Background/Aims: Chondrocyte apoptosis is largely responsible for cartilage degeneration in osteoarthritis (OA). Interleukin-1 beta (IL-1β) is widely used as a chondrocyte apoptosis-inducing agent, while lactoferrin (LF) is an anabolic reagent which has the potential to inhibit chondrocyte apoptosis. We assessed the effects of LF on cartilage degeneration in IL-1β-induced chondrocytes and in a rat model of OA, and explored the potential molecular mechanisms involved. Methods: Human articular chondrocytes (HACs) were treated with IL-1β alone or in combination with LF. MTT and flow cytometric assays were used to detect changes after treatment with LF. Western blotting was used to examine the relevant molecules regulating apoptosis. Results: We found that IL-1β reduced the viability of HACs, whereas 200 μg/mL of LF significantly counteracted the inhibitory effect of IL-1β. LF significantly inhibited IL-1β-induced HAC apoptosis. The protein expression of the apoptotic markers Caspase-3 and PARP was also significantly reduced in the LF treatment group when analyzed by western blotting. Furthermore, we found that LF triggered CREB1 phosphorylation in IL-1β-induced HAC apoptosis through AKT1 signaling. In addition, LF promoted the repair of articular cartilage damage in a rat OA model with elevated p-CREB levels. Conclusions: These studies suggest that LF has an anti-apoptotic effect on IL-1β-induced chondrocytes, and thus may be a promising novel therapeutic agent for OA.

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