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Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.

ABSTRACT: Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4472123 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Targeting cartilage EGFR pathway for osteoarthritis treatment.

Project description:Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

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Project description:Osteoarthritis (OA) is a type of joint disease associated with wear and tear, inflammation, and aging. Mechanical stress along with synovial inflammation promotes the degradation of the extracellular matrix in the cartilage, leading to the breakdown of joint cartilage. The nuclear factor-kappaB (NF-?B) transcription factor has long been recognized as a disease-contributing factor and, thus, has become a therapeutic target for OA. Because NF-?B is a versatile and multi-functional transcription factor involved in various biological processes, a comprehensive understanding of the functions or regulation of NF-?B in the OA pathology will aid in the development of targeted therapeutic strategies to protect the cartilage from OA damage and reduce the risk of potential side-effects. In this review, we discuss the roles of NF-?B in OA chondrocytes and related signaling pathways, including recent findings, to better understand pathological cartilage remodeling and provide potential therapeutic targets that can interfere with NF-?B signaling for OA treatment.

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2024-07-31 | GSE271151 | GEO

Quercetin Modulates Ferroptosis via the SIRT1/Nrf−2/HO−1 Pathway and Attenuates Cartilage Destruction in an Osteoarthritis Rat Model

Project description: Not available

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Differential gene expression in cartilage from the mouse DMM osteoarthritis model

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2013-04-11 | E-GEOD-45793 | biostudies-arrayexpress

MCC950, the NLRP3 Inhibitor, Protects against Cartilage Degradation in a Mouse Model of Osteoarthritis.

Project description:Osteoarthritis (OA), characterized by chronic systemic low-level inflammation and cartilage degeneration, is a type of arthritis closely associated with aging. Inflammation and aging play a pivotal role in the occurrence and progression of OA. NLRP3 inflammasome is involved in many inflammatory and aging diseases, and NLRP3 inhibitor MCC950 has anti-inflammatory and antisenescence effects on some diseases such as Alzheimer's disease. In the present study, we found that NLRP3 protein was upregulated in human and mouse OA cartilage. Moreover, NLRP3 and Caspase1 expression induced by IL-1β in chondrocytes was blocked by MCC950. In addition, MCC950 inhibited the expression of inflammatory mediators, matrix-degrading enzymes, senescence marker protein P16 (INK4A), and β-galactosidase, as well as excessive production of ROS. Meanwhile, MCC950 promoted autophagy-related protein expression and autophagy flux under the inflammatory condition. However, autophagy inhibitor 3-MA reversed anti-inflammatory and anticatabolic effects of MCC950. In in vivo experiments, intra-articular administration of MCC950 further showed its protective effect on cartilage degeneration. Bioinformatic analysis and in vitro experimental results revealed that MCC950 might play a protective role in cartilage by regulating Nrf2/HO-1/NQO1, PI3k/Akt/mTOR, P38/MAPK, and JNK/MAPK pathways. In conclusion, our work demonstrated that NLRP3 inhibitor MCC950 might serve as a promising strategy for OA treatment.

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Differential gene expression in cartilage from the mouse DMM osteoarthritis model

2013-04-11 | GSE45793 | GEO

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

Project description:ObjectivesWhile various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.MethodsCcl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.ResultsMice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.ConclusionsOur findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

| S-EPMC5834918 | biostudies-literature

Prokineticin 2 is a catabolic regulator of osteoarthritic cartilage destruction in mouse.

Project description:BackgroundOur preliminary study indicates that the multi-functional protein, prokineticin 2 (Prok2), is upregulated in osteoarthritic (OA) chondrocytes as a target of the hypoxia-inducible factor (HIF)-2α. This study aims to elucidate the potential roles of Prok2 in OA.MethodsProk2 expression was assessed through microarray analysis in chondrocytes and confirmed via immunostaining in OA cartilage. Experimental OA was induced through destabilization of the medial meniscus (DMM). Functions of Prok2 were assessed by adenoviral overexpression, intra-articular (IA) injection of recombinant Prok2 (rProk2), and knockdown of Prok2 in joint tissues. We also explored the potential utility of Prok2 as an OA biomarker using enzyme-linked immunosorbent assay (ELISA).ResultsHIF-2α upregulated Prok2, one of the prokineticin signaling components, in OA chondrocytes of mice and humans. Adenoviral overexpression of Prok2 in chondrocytes and cartilage explants, as well as the application of rProk2, led to an upregulation of matrix metalloproteinase (MMP)3 and MMP13. Consistently, the overexpression of Prok2 in joint tissues or IA injection of rProk2 exacerbated cartilage destruction and hindpaw mechanical allodynia induced by DMM. However, the knockdown of Prok2 in joint tissues did not significantly affect DMM-induced cartilage destruction. Additionally, despite being a secreted protein, the serum levels of Prok2 in OA mice and human OA patients were found to be below the range detected by ELISA.ConclusionThe upregulation of Prok2 exacerbates OA cartilage destruction and hindpaw mechanical allodynia. However, its knockdown is not sufficient to inhibit experimental OA and Prok2 is not a potential candidate serum biomarker of OA.

| S-EPMC10699050 | biostudies-literature

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