The immune microenvironment in cartilage injury and repair

Acta Biomaterialia, Journal Year: 2021, Volume and Issue: 140, P. 23 - 42

Published: Dec. 10, 2021

The ability of articular cartilage to repair itself is limited because it lacks blood vessels, nerves, and lymph tissue. Once damaged, can lead joint swelling pain, accelerating the progression osteoarthritis. To date, complete regeneration hyaline exhibiting mechanical properties remains an elusive goal, despite many available technologies. inflammatory milieu created by damage critical for chondrocyte death hypertrophy, extracellular matrix breakdown, ectopic bone formation, injury In microenvironment, mesenchymal stem cells (MSCs) undergo aberrant differentiation, chondrocytes begin convert or dedifferentiate into with a fibroblast phenotype, thereby resulting in fibrocartilage poor qualities. All these factors suggest that problems may be major stumbling block repair. produce conducive repair, multi-dimensional management microenvironment place time required. Therefore, this calls elucidation immune after injury. This review provides brief overview of: (1) pathogenesis injury; (2) repair; (3) effects cytokines on (4) clinical strategies treating defects; (5) targeted immunoregulation Immune response increasingly considered key factor affecting It has both negative positive regulatory process Proinflammatory are secreted large numbers, necrotic removed. During period, secrete anti-inflammatory chondrogenic cytokines, which inhibit inflammation promote However, persist, accelerate degradation matrix. Furthermore, MSCs abnormal transform fibroblast-like cells, forming properties. Consequently, requires regulation space make regeneration.

Language: Английский

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The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Drug Design Development and Therapy, Journal Year: 2021, Volume and Issue: Volume 15, P. 2921 - 2945

Published: July 1, 2021

Abstract: Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved disease-modifying drugs (DMOADs). In this review, we discuss the reasons necessitating development DMOADs for OA management, classifications clinical phenotypes or molecular/mechanistic endotypes from viewpoint targeted drug discovery, then summarize efficacy safety profile range in Phase 2 3 trials directed to cartilage-driven, bone-driven, inflammation-driven endotypes. Finally, briefly put forward failures possible steps overcome these barriers. Keywords: osteoarthritis, DMOADs, drugs, intra-articular therapy, phenotype, endotype

Language: Английский

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Cell Membrane-Coated Mimics: A Methodological Approach for Fabrication, Characterization for Therapeutic Applications, and Challenges for Clinical Translation

ACS Nano, Journal Year: 2021, Volume and Issue: 15(11), P. 17080 - 17123

Published: Oct. 26, 2021

Cell membrane-coated (CMC) mimics are micro/nanosystems that combine an isolated cell membrane and a template of choice to mimic the functions cell. The design exploits its physicochemical biological properties for therapeutic applications. demonstrate excellent compatibility, enhanced biointerfacing capabilities, physical, chemical, tunability, ability retain cellular properties, immune escape, prolonged circulation time, protect encapsulated drug from degradation active targeting. These ease adapting them personalized clinical medicine have generated significant research interest over past decade. This review presents detailed overview recent advances in development mimics. primary focus is collate discuss components, fabrication methodologies, significance physiochemical characterization techniques validating CMC mimic. We present critical analysis two main components mimics: mapped their use scenarios. In addition, we emphasized on challenges associated with translation. Overall, this up date toolbox researchers can benefit while designing characterizing

Language: Английский

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Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

Science Advances, Journal Year: 2023, Volume and Issue: 9(14)

Published: April 5, 2023

Abnormal subchondral bone remodeling featured by overactivated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is unclear. We used lymphocyte cytosolic protein 1 (Lcp1) knockout mice suppress osteoclasts in a OA model with anterior cruciate ligament transection (ACLT), Lcp1-/- showed decreased retarded degeneration. For mechanisms, activated induced type-H vessels elevated oxygen concentration, which ubiquitylated hypoxia-inducible factor alpha subunit (HIF-1α) chondrocytes led Lcp1 impeded angiogenesis, maintained hypoxia environment joints delayed progression. Stabilization of HIF-1α degeneration, knockdown Hif1a abolished protective effects knockout. Last, we that Oroxylin A, an Lcp1-encoded l-plastin (LPL) inhibitor, could alleviate In conclusion, maintaining hypoxic attractive strategy for treatment.

Language: Английский

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Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 10, 2022

Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism chondrocyte senescence osteoarthritis pathophysiology remain largely undefined. Here we show that deficiency exaggerates progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization medial meniscus-induced Mechanistically, can directly interact with STAT5 deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed deacetylated conserved lysine 163 on STAT5. Mutation arginine abolished regulatory effect Sirt6. In vivo, specific ablation chondrocytes exacerbated Pharmacological activation substantially alleviated senescence. Taken together, by Targeting represents promising new approach for

Language: Английский

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Cartilage calcification in osteoarthritis: mechanisms and clinical relevance

Nature Reviews Rheumatology, Journal Year: 2022, Volume and Issue: 19(1), P. 10 - 27

Published: Dec. 12, 2022

Language: Английский

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Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies

International Journal of Oral Science, Journal Year: 2022, Volume and Issue: 14(1)

Published: Aug. 5, 2022

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for major source of pain disability worldwide. However, effective strategies repair are lacking, patients with advanced OA usually need replacement. Better comprehending pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as new means cell-to-cell communication delivering multiple bioactive molecules create particular microenvironment tunes behavior. Specifically, exosome cargos, such noncoding RNAs (ncRNAs) proteins, play crucial role in progression regulating the proliferation, apoptosis, autophagy, inflammatory response cells, rendering them promising candidates monitoring treatment. This review systematically summarizes current insight regarding biogenesis function their potential therapeutic tools targeting OA, suggesting realms improve management.

Language: Английский

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Targeted and responsive biomaterials in osteoarthritis

Theranostics, Journal Year: 2023, Volume and Issue: 13(3), P. 931 - 954

Published: Jan. 1, 2023

Osteoarthritis (OA) is a degenerative disease characterized by loss of articular cartilage and chronic inflammation, involving multiple cellular dysfunctions tissue lesions.The non-vascular environment dense matrix in the joints tend to block drug penetration, resulting low bioavailability.There desire develop safer more effective OA therapies meet challenges an aging world population future.Biomaterials have achieved satisfactory results improving targeting, prolonging duration action, achieving precision therapy.This article reviews current basic understanding pathological mechanisms clinical treatment dilemmas OA, summarizes discusses advances for different kinds targeted responsive biomaterials seeking provide new perspectives OA.Subsequently, limitations translation biosafety are analyzed guide development future therapeutic strategies OA.As need medicine rises over time, emerging multifunctional based on targeting controlled release will become irreplaceable part management.

Language: Английский

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Hallmarks of peripheral nerve function in bone regeneration

Bone Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: Jan. 5, 2023

Abstract Skeletal tissue is highly innervated. Although different types of nerves have been recently identified in the bone, crosstalk between bone and remains unclear. In this review, we outline role peripheral nervous system (PNS) regeneration following injury. We first introduce conserved species ranging from amphibians to mammals. then present distribution PNS skeletal under physiological conditions, fractures, or regeneration. Furthermore, summarize ways which communicates with bone-lineage cells, vasculature, immune cells microenvironment. Based on comprehensive timely conclude that regulates through neuropeptides neurotransmitters nerves. An in-depth understanding roles will inform development new strategies based bone-nerve promoting repair

Language: Английский

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Forkhead box O3 attenuates osteoarthritis by suppressing ferroptosis through inactivation of NF-κB/MAPK signaling

Journal of Orthopaedic Translation, Journal Year: 2023, Volume and Issue: 39, P. 147 - 162

Published: March 1, 2023

Ferroptosis is a nonapoptotic cell death process that characterized by lipid peroxidation and intracellular iron accumulation. As osteoarthritis (OA) progresses, inflammation or overload induces ferroptosis of chondrocytes. However, the genes play vital role in this are still poorly studied.Ferroptosis was elicited ATDC5 chondrocyte line primary chondrocytes administration proinflammatory cytokines, interleukin (IL)-1β tumor necrosis factor (TNF)-α, which key roles OA. The effect FOXO3 expression on apoptosis, extracellular matrix (ECM) metabolism, cells verified western blot, Immunohistochemistry (IMHC), immunofluorescence (IF) measuring Malondialdehyde (MDA) Glutathione (GSH) levels. signal cascades modulated FOXO3-mediated were identified using chemical agonists/antagonists lentivirus. In vivo experiments performed following destabilization medial meniscus surgery 8-week-old C57BL/6 mice included micro-computed tomography measurements.In vitro IL-1β TNF-α, to induced ferroptosis. addition, agonist, erastin, inhibitor, ferrostatin-1, downregulated upregulated protein forkhead box O3 (FOXO3), respectively. This, suggested, for first time, may regulate articular cartilage. Our results further suggested regulated ECM metabolism via mechanism Moreover, NF-κB/mitogen-activated kinase (MAPK) signaling cascade regulating demonstrated. confirmed rescue intra-articular injection FOXO3-overexpressing lentivirus against erastin-aggravated OA.The our study show activation promotes disrupts both vitro. can reduce OA progression inhibiting through NF-κB/MAPK pathway.This highlights important inhibition activating expected be new target treatment

Language: Английский

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