Promote Cartilage Repair Research Articles

Extreme examples of reparative chondrogenesis: molecular mechanisms

Restoring hyaline cartilage integrity remains a significant challenge in regenerative medicine. When damaged, the defect is replaced by fibrosis connective tissue, resulting in a loss of the biomechanical properties of the cartilage. This review examines the intricate molecular mechanisms underlying reparative chondrogenesis and presents examples from a variety of animal species. It provides a comprehensive overview of the signaling pathways and cellular responses that promote cartilage repair, showcasing the regenerative abilities of fish and amphibians, including the little skate and axolotl, and surprising cases of chondrogenesis in mammals like the naked mole-rat and the Acomys mouse. Unraveling the dynamic interplay between growth factors, cytokines, and extracellular matrix components will shed light on the complex signaling pathways controlling reparative chondrogenesis. The comparative analysis presented in this review reveals both conserved and species-specific molecular pathways involved in cartilage regeneration. This provides valuable information for translational studies. By uncovering the genetic and epigenetic determinants governing extreme examples of reparative chondrogenesis, this review provides a comprehensive framework for developing therapeutic strategies to improve cartilage repair in humans.

Exosomes derived from platelet-rich plasma present a novel potential in repairing knee articular cartilage defect combined with cyclic peptide-modified β-TCP scaffold

BackgroundThe aim of this study was to investigate the therapeutic effects and mechanisms of PRP-exos combined with cyclic peptide-modified β-TCP scaffold in the treatment of rabbit knee cartilage defect.MethodsPRP-exos were extracted and characterized by TEM, NTA and WB. The therapeutic effects were evaluated by ICRS score, HE staining, Immunohistochemistry, qRT-PCR and ELISA. The repair mechanism of PRP-exos was estimated and predicted by miRNA sequencing analysis and protein–protein interaction network analysis.ResultsThe results showed that PRP-exos had a reasonable size distribution and exhibited typical exosome morphology. The combination of PRP-exos and cyclic peptide-modified β-TCP scaffold improved ICRS score and the expression level of COL-2, RUNX2, and SOX9. Moreover, this combination therapy reduced the level of MMP-3, TNF-α, IL-1β, and IL-6, while increasing the level of TIMP-1. In PRP-exos miRNA sequencing analysis, the total number of known miRNAs aligned across all samples was 252, and a total of 91 differentially expressed miRNAs were detected. The results of KEGG enrichment analysis and the protein–protein interaction network analysis indicated that the PI3K/AKT signaling pathway could impact the function of chondrocytes by regulating key transcription factors to repair cartilage defect.ConclusionPRP-exos combined with cyclic peptide-modified β-TCP scaffold effectively promoted cartilage repair and improved chondrocyte function in rabbit knee cartilage defect. Based on the analysis and prediction of PRP-exos miRNAs sequencing, PI3K/AKT signaling pathway may contribute to the therapeutic effect. These findings provide experimental evidence for the application of PRP-exos in the treatment of cartilage defect.

Advancing Osteoarthritis Treatment: The Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes and Biomaterial Integration

Background/Objectives: Osteoarthritis (OA) is a prevalent and debilitating joint disorder characterized by progressive cartilage degradation and inflammation, for which traditional treatments offer only symptomatic relief without halting disease progression. Exosomes, cell-free vesicles derived from mesenchymal stem cells, have emerged as a promising alternative therapy owing to their regenerative and anti-inflammatory properties. Methods: This review synthesizes findings from recent studies (2017–2023) on the therapeutic potential of exosomes in OA treatment, highlighting their ability to modulate the joint microenvironment, reduce inflammation, and promote cartilage repair by delivering bioactive molecules such as cytokines, growth factors, and regulatory ribonucleic acids. Results: We explore the integration of exosomes with biomaterials, such as hydrogels and scaffolds, to enhance their delivery and therapeutic efficacy, and we address the critical challenges associated with their clinical application, including standardization of isolation and characterization methods, scalability of production, mechanistic understanding, and long-term safety. Despite these challenges, exosome-based therapies offer several advantages over traditional and cell-based treatments, including lower immunogenicity, ease of handling, and targeted delivery of therapeutic agents to damaged tissues. Conclusions: We provide an analytical perspective on the current state of exosome research in OA, emphasizing the need for standardized production methods, deeper mechanistic insights, and rigorous long-term safety assessments. Future directions should focus on optimizing delivery systems, exploring personalized medicine approaches, and conducting comparative effectiveness studies to fully realize the potential of exosome therapies for OA treatment. Addressing these gaps will be crucial for translating exosome therapies from bench to bedside and achieving a transformative impact on OA management.

The Therapeutic Potential of Adipose-Derived Mesenchymal Stem Cell Secretome in Osteoarthritis: A Comprehensive Study

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms.

The role of fibrinogen combined with platelet-rich plasma in enhancing microfracture for cartilage damage: a retrospective study of 113 patients with knee osteoarthritis

ObjectiveKnee osteoarthritis is the most common osteoarthritis and imposes a significant burden on patients’ lives. Several treatment methods can promote cartilage repair to varying extents, but there are limited studies on the combined application of different treatments. The purpose of this study is to evaluate the clinical efficacy of microfracture combined with fibrinogen and platelet-rich plasma (PRP) under arthroscopic in treating knee osteoarthritis, so as to provide a basis for clinical treatment decisions.MethodA total of 113 patients with knee osteoarthritis who received orthopedic treatment from January 2021 to June 2022 were selected. They were divided into two groups according to whether they received fibrinogen and PRP treatment in addition to microfracture treatment. The two groups were analyzed to compare the differences in knee joint function and quality of life at different points.ResultsThe study compared changes in knee joint function scores and quality of life between the two groups after treatment and found that the quality of life of patients in the combined treatment group was significantly better than that of patients who received microfracture only (at 12-month follow-up, EuroQol-VAS scores were 64.32 ± 5.63 for the microfracture group (MFx) and 75.65 ± 8.57 for the fibrinogen combined with platelet-rich plasma-assisted microfracture group (FPRPA MFx); P = 0.015; at 24-month follow-up, EuroQol-VAS scores were 66.47 ± 5.18 for the MFx group and 79.40 ± 7.43 for the FPRPA MFx group, P = 0.022). There was also a strong correlation between patients’ quality of life and knee joint function score index (IKDC score correlation coefficient r=-0.375, Lysholm score correlation coefficient r = 0.497, MOCART score correlation coefficient r = 0.579, VAS score correlation coefficient r = 0.242, T2 value correlation coefficient r=-0.293, P < 0.001). Age-stratified analysis of the patients in the microfracture combined with fibrinogen platelet-rich plasma treatment group showed that the effect of the combined treatment was more pronounced in elderly patients.ConclusionsThe results of the study showed that compared with microfracture alone, microfracture combined with fibrinogen platelet-rich plasma therapy can further improve patients’ knee joint-related function and their quality of life after treatment. The improvement was more obvious in elderly patients.

Therapeutic Effects of Puerarin Loaded Bone Marrow Mesenchymal Stem Cell-Derived Exosomes in a Rat Model of Osteoarthritis.

Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease among the aged population. The primary objective of this study was to assess the therapeutic potential of puerarin loaded bone marrow mesenchymal stem cell-derived exosomes (Pue@BMSC-Exo), and reveal their inflammatory regulating mechanisms through affecting the nuclear factor kappa-B (NF-κB) signaling pathway. In this study, exosomes derived from BMSCs were isolated and identified. Cell proliferation and migration were evaluated by CCK-8 and scratch methods. Furthermore, histological and micro-computed tomography analysis were performed to assess alterations of articular cartilage in OA rats. Results showed that BMSC-Exo and Pue@BMSC-Exo conformed with the basic characteristics of exosomes. BMSC-Exo increased the solubility of Pue and enhanced drug uptake by chondrocytes. In addition, Pue@BMSC-Exo stimulated proliferation and migration of chondrocyte, and also promoted cartilage repair by reducing matrix metalloproteinase MMP13 production and increasing type II collagen (Col2) synthesis. Furthermore, Pue@BMSC-Exo, by effectively inhibiting the NF-κB signaling pathway, reduced the production of inflammatory mediators and attenuated the release of the inflammatory marker nitric oxide (NO), ultimately ameliorating the damage of chondrocyte. These findings exhibited the potential therapeutic significance of Pue@BMSC-Exo in OA and warranted further exploration in clinical applications.

Role and mechanism of Actein on condylar bone metabolism in APOE deletion-induced osteoporotic mice

AimsTo investigate the effects of Actein from Cimicifugae Rhizoma on condylar bone and cartilage in APOE deletion-induced osteoporotic mice, and to preliminarily explore the underlying mechanism. MethodsSixty 8-week-old female mice were used, which underwent APOE−/− and ovariectomy procedures, followed by oral administration of Actein (15 mg/kg) and Atorvastatin Calcium (AC, 3 mg/kg) for eight weeks. Body weight, uterine weight, and systemic indexes related to bone metabolism and lipid metabolism were assessed in each group. Changes in condylar bone histomorphometric parameters were evaluated using Micro-CT. Morphological changes in the condyle were observed with Hematoxylin-Eosin (H&E), Safranin O/Fast Green, and Alcian Blue Hematoxylin/Orange G (ABH/OG) staining, with OARSI pathology scoring performed. Sirius red staining and immunofluorescence were used to determine the expression levels of Collagen I (Col I) and Collagen III (Col III) in bone matrix, and Col II in cartilage matrix. Immunohistochemistry assessed the relative expression levels of ALP and proteins associated with the Wnt/β-catenin/RUNX2 signaling pathway. ResultsAPOE−/− exacerbates ovariectomy -induced osteoporosis (OP) in condylar of mice. Actein and AC significantly reversed OP, improved bone mineral density (BMD), increased bone microarchitecture, and restored abnormal calcium and phosphorus metabolism in the blood and urine. Morphologically, APOE−/− and ovariectomy reduced condylar cartilage thickness, disrupted chondrocyte arrangement, chondrocyte cleavage, and clustered aggregation, resembling osteoarthritis (OA)-like changes. Actein and AC partially restored the disrupted chondrocyte arrangement, smoothed chondrocyte cleavage, and up-regulated the levels of chondrocyte matrix (Col II, aggrecan) and bone matrix (Col III, ALP). Actein reversed the OA process, potentially through the Wnt/β-catenin/RUNX2 signaling pathway. ConclusionAPOE−/− and ovariectomy induced OP, leading to OA-like lesions in condylar of mice. Actein promoted cartilage repair and trabecular bone recovery by increasing extracellular matrix synthesis (Col II, Col III, aggrecan), reversing the OA process, possibly through the Wnt/β-catenin/RUNX2 signaling pathway.

Lubricant Strategies in Osteoarthritis Treatment: Transitioning from Natural Lubricants to Drug Delivery Particles with Lubricant Properties.

Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degradation, leading to pain and functional impairment. A key contributor to OA progression is the decline in cartilage lubrication. In physiological conditions, synovial fluid (SF) macromolecules like hyaluronic acid (HA), phospholipids, and lubricin play a crucial role in the boundary lubrication of articular cartilage. In early OA, cartilage damage triggers inflammation, altering SF composition and compromising the lubrication layer. This increases friction between mating interfaces, worsening cartilage degradation and local inflammation. Therefore, early-stage restoration of lubrication (by injecting in the joint different classes of compounds and formulations) could alleviate, and potentially reverse, OA progression. In the light of this, a broad variety of lubricants have been investigated for their ability to reduce friction in OA joints and promote cartilage repair in clinical and preclinical studies. This review examines recent advancements in lubricant-based therapy for OA, focusing on natural, bioinspired, and alternative products. Starting from the currently applied therapy, mainly based on natural lubricants as HA, we will present their modified versions, either in hydrogel form or with specific biomimetic moieties with the aim of reducing their clearance from the joint and of enhancing their lubricating properties. Finally, the most advanced and recent formulation, represented by alternative strategies, will be proposed. Particular emphasis will be placed on those ones involving new types of hydrogels, microparticles, nanoparticles, and liposomes, which are currently under investigation in preclinical studies. The potential application of particles and liposomes could foster the transition from natural lubricants to Drug Delivery Systems (DDSs) with lubricant features; transition which could provide more complete OA treatments, by simultaneously providing lubrication replacement and sustained release of different payloads and active agents directly at the joint level. Within each category, we will examine relevant preclinical studies, highlighting challenges and future prospects.

Lesion-localized hydrogels functionalized with engineered extracellular matrix restore cellular homeostasis by enhancing mitochondrial energy metabolism for osteoarthritis therapy

Cartilage damage and degeneration are fundamental pathological features of osteoarthritis (OA), attributed largely to disruptions in chondrocyte homeostasis. Tissue engineering employing functional bioactive materials presents a promising avenue for cartilage regeneration and repair. Particularly, extracellular matrix (ECM) produced by mesenchymal stem cells (MSCs) is gaining traction in the field of tissue engineering and scaffold-based regenerative therapies due to its robust bioactivity and excellent biocompatibility. In this study, we utilized specific inflammatory cytokines associated with OA as stimulators to optimize the MSC-derived secretome. Our in vitro experiments demonstrated that the engineered ECM effectively inhibited early chondrocyte apoptosis, reversed cellular senescence, and maintained anabolic-catabolic equilibrium. Moreover, we developed aldehyde- and methacrylic anhydride-modified hyaluronic acid hydrogels incorporated with ECM (ECM@AH) using photo-cross-linking techniques. The affinity of these ECM-functionalized hydrogels for degraded cartilage was confirmed through in situ cartilage lesion localization experiments in the knee joints of rat OA models. Further in vitro analysis revealed that the engineered ECM@AH, especially IFN-γ-ECM@AH, sustains chondrocyte homeostasis by restoring mitochondrial energy metabolism. Animal studies demonstrated that ECM@AH, localized to cartilage lesions, could reverse cartilage matrix degradation and promote cartilage repair, underscoring the potential of this biomaterial in OA treatment.

Enhancing Cartilage Repair: Surgical Approaches, Orthobiologics, and the Promise of Exosomes.

Treating cartilage damage is challenging as its ability for self-regeneration is limited. Left untreated, it can progress to osteoarthritis (OA), a joint disorder characterized by the deterioration of articular cartilage and other joint tissues. Surgical options, such as microfracture and cell/tissue transplantation, have shown promise as techniques to harness the body's endogenous regenerative capabilities to promote cartilage repair. Nonetheless, these techniques have been scrutinized due to reported inconsistencies in long-term outcomes and the tendency for the defects to regenerate as fibrocartilage instead of the smooth hyaline cartilage native to joint surfaces. Orthobiologics are medical therapies that utilize biologically derived substances to augment musculoskeletal healing. These treatments are rising in popularity because of their potential to enhance surgical standards of care. More recent developments in orthobiologics have focused on the role of exosomes in articular cartilage repair. Exosomes are nano-sized extracellular vesicles containing cargo such as proteins, lipids, and nucleic acids, and are known to facilitate intercellular communication, though their regenerative potential still needs to be fully understood. This review aims to demonstrate the advancements in cartilage regeneration, highlight surgical and biological treatment options, and discuss the recent strides in understanding the precise mechanisms of action involved.

A chondroitin sulphate hydrogel with sustained release of SDF-1α for extensive cartilage defect repair through induction of cell homing and promotion of chondrogenesis.

Articular cartilage damage represents a prevalent clinical disease in orthopedics, with its regeneration and repair constituting a central focus in ongoing research endeavors. While hydrogel technology has achieved notable progress in the field of cartilage regeneration, addressing the repair of larger cartilage defects remains a significant and formidable challenge. In pursuit of achieving the repair of extensive cartilage defects, this study designed a polydopamine-modified chondroitin sulfate hydrogel loaded with SDF-1α (P-SCMA). This hydrogel, capable of directly providing glycosaminoglycans (GAGs), served as a platform for carrying growth factors and attracting mesenchymal stem cells for the in situ reconstruction of extensive cartilage defects. The results indicate that the P-SCMA hydrogel is capable of not only directly providing GAGs but also sustainably releasing SDF-1α. In the early stages, it promotes cell adhesion and proliferation and induces cell homing, while in the later stages, it further induces chondrogenesis by inhibiting the Wnt/β-catenin pathway. This bioactive hydrogel, which possesses the functions of providing GAGs, promoting cell proliferation, inducing cell homing and chondrogenesis, is capable of promoting cartilage repair in multiple ways, providing new perspectives for the repair of extensive cartilage defects.

Stem cell recruitment polypeptide hydrogel microcarriers with exosome delivery for osteoarthritis treatment

With the accelerated aging tendency, osteoarthritis (OA) has become an intractable global public health challenge. Stem cells and their derivative exosome (Exo) have shown great potential in OA treatment. Research in this area tends to develop functional microcarriers for stem cell and Exo delivery to improve the therapeutic effect. Herein, we develop a novel system of Exo-encapsulated stem cell-recruitment hydrogel microcarriers from liquid nitrogen-assisted microfluidic electrospray for OA treatment. Benefited from the advanced droplet generation capability of microfluidics and mild cryogelation procedure, the resultant particles show uniform size dispersion and excellent biocompatibility. Moreover, acryloylated stem cell recruitment peptides SKPPGTSS are directly crosslinked within the particles by ultraviolet irradiation, thus simplifying the peptide coupling process and preventing its premature release. The SKPPGTSS-modified particles can recruit endogenous stem cells to promote cartilage repair and the released Exo from the particles further enhances the cartilage repair performance through synergistic effects. These features suggest that the proposed hydrogel microcarrier delivery system is a promising candidate for OA treatment.

Curcumenol regulates Histone H3K27me3 demethylases KDM6B affecting Succinic acid metabolism to alleviate cartilage degeneration in knee osteoarthritis

BackgroundCartilage metabolism dysregulation is a crucial driver in knee osteoarthritis (KOA). Modulating the homeostasis can mitigate the cartilage degeneration in KOA. Curcumenol, derived from traditional Chinese medicine Curcuma Longa L., has demonstrated potential in enhancing chondrocyte proliferation and reducing apoptosis. However, the specific mechanism of Curcumenol in treating KOA remains unclear. This study aimed to demonstrate the molecular mechanism of Curcumenol in treating KOA based on the transcriptomics and metabolomics, and both in vivo and in vitro experimental validations. Materials and methodsIn this study, a destabilization medial meniscus (DMM)-induced KOA mouse model was established. And the mice were intraperitoneally injected with Curcumenol at 4 and 8 mg/kg concentrations. The effects of Curcumenol on KOA cartilage and subchondral was evaluated using micro-CT, histopathology, and immunohistochemistry (IHC). In vitro, OA chondrocytes were induced with 10 μg/mL lipopolysaccharide (LPS) and treated with Curcumenol to evaluate the proliferation, apoptosis, and extracellular matrix (ECM) metabolism through CCK8 assay, flow cytometry, and chondrocyte staining. Furthermore, transcriptomics and metabolomics were utilized to identify differentially expressed genes (DEGs) and metabolites. Finally, integrating multi-omics analysis, virtual molecular docking (VMD), and molecular dynamics simulation (MDS), IHC, immunofluorescence (IF), PCR, and Western blot (WB) validation were conducted to elucidate the mechanism by which Curcumenol ameliorates KOA cartilage degeneration. ResultsCurcumenol ameliorated cartilage destruction and subchondral bone loss in KOA mice, promoted cartilage repair, upregulated the expression of COL2 while downregulated MMP3, and improved ECM synthesis metabolism. Additionally, Curcumenol also alleviated the damage of LPS on the proliferation activity and suppressed apoptosis, promoted ECM synthesis. Transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified a significant downregulation of 19 key genes in KOA. Metabolomic profiling showed that Curcumenol downregulates the expression of d-Alanyl-d-alanine, 17a-Estradiol, Glutathione, and Succinic acid, while upregulating Sterculic acid and Azelaic acid. The integrated multi-omics analysis suggested that Curcumenol targeted KDM6B to regulate downstream protein H3K27me3 expression, which inhibited methylation at the histone H3K27, consequently reducing Succinic acid levels and improving KOA cartilage metabolism homeostasis. Finally, both in vivo and in vitro findings indicated that Curcumenol upregulated KDM6B, suppressed H3K27me3 expression, and stimulated collagen II expression and ECM synthesis, thus maintaining cartilage metabolism homeostasis and alleviating KOA cartilage degeneration. ConclusionCurcumenol promotes cartilage repair and ameliorates cartilage degeneration in KOA by upregulating KDM6B expression, thereby reducing H3K27 methylation and downregulating Succinic Acid, restoring metabolic stability and ECM synthesis.

Magnetic Polysaccharide Mesenchymal Stem Cells Exosomes Delivery Microcarriers for Synergistic Therapy of Osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative disease that afflicts more than 250 million people worldwide, impairing their mobility and quality of life. However, conventional drug therapy is palliative. Exosomes (Exo), although with the potential to fundamentally repair cartilage, face challenges in their efficient enrichment and delivery. In this study, we developed magnetic polysaccharide hydrogel particles as microcarriers for synergistic therapy of OA. The microcarriers were composed of modified natural polysaccharides, hyaluronic acid (HAMA), and chondroitin sulfate (CSMA), and were generated from microfluidic electrospray in combination with a cryogelation process. Magnetic nanoparticles with spiny structures capable of capturing stem cell Exo were encapsulated within the microcarriers together with an anti-inflammatory drug diclofenac sodium (DS). The released DS and Exo from the microcarriers had a synergistic effect in alleviating the OA symptoms and promoting cartilage repair. The in vitro and in vivo results demonstrated the excellent performance of the microcarrier for OA treatment. We believe this work has potential for Exo therapy of OA and other related diseases.

Synovial Lubrication Factors‐Recruiting Biomimetic Polyphenolized Hyaluronic Acid for Promoting Cartilage Repair

AbstractOsteoarthritis is a common degenerative disease characterized by continuous detachment of lubrication factors from damaged cartilage matrix. This study proposes a paradigm that combines natural polyanionic polysaccharides (hyaluronic acid, HA) with dopamine (DA) to design a synovial lubrication factors‐recruiting biomimetic polyphenolized lubrication system. The biomimetic lubricants can use DA's polarity and hydrophilic groups as specific binding sites of type II collagen's polarity and hydrophilic groups to stably bind cartilage surface, and further utilize molecular specific interaction to recruit detached, joint endogenous or chondrocytes expressed synovial lubrication factors, continuously forming supramolecular lubrication complex onto cartilage matrix to induce joint lubrication. Simultaneously, the biolubricants can also utilize catechol groups to eliminate anionic free radicals and resist reactive oxygen species invasion in the early stages of joint lubrication failure. The prepared biolubricants exhibit low coefficient of friction (µ &lt; 0.08), which is attributed to fluid and hydration lubrication provided by HA and DA side chains through fluid dynamic effect and interfacial hydration adsorption. Cell and animal experiments also demonstrate polyphenolic biolubricants have good biocompatibility and promote cartilage regeneration. Therefore, the developed synovial lubricants‐recruiting biomimetic polyphenolized biolubricants have potential for treating osteoarthritis, and also provide a theoretical basis for other biological tissues with lubrication problems.

Simultaneously Modulating HIF-1α and HIF-2α and Optimizing Macrophage Polarization through the Biomimetic Gene Vector toward the Treatment of Osteoarthritis.

In osteoarthritis (OA), articular cartilage is continuously submerged in a hypoxic environment throughout life, and hypoxia-inducible factors (HIFs) play a crucial role in OA progression. Among the various HIF phenotypes, HIF-1α positively contributes to maintaining the stability of the articular cartilage matrix. In contrast, HIF-2α has a detrimental effect, leading to chondrocyte apoptosis and exacerbating inflammation. Notably, there is currently no simultaneous regulation of HIF-1α and HIF-2α for OA treatment. Thus, the biomimetic gene vector (MENP) was developed for co-delivery of siHIF-2α and Mg2+ to the inflamed regions in OA joints, comprising an inner core consisting of siHIF-2α and Mg2+ and an outer M2 macrophage membrane. Invitro and invivo studies demonstrate that MENP effectively targets inflamed areas, efficiently silences HIF-2α, and facilitates HIF-1α-mediated cartilage restoration through Mg2+. Furthermore, it indirectly promotes the polarization of macrophages toward an anti-inflammatory M2 phenotype through its action on inflamed synoviocytes. Overall, MENP is an efficient biomimetic vehicle for alleviating inflammation and promoting cartilage repair, representing an appealing approach for OA treatment.

Injectable porous microspheres for articular cartilage regeneration through in situ stem cell recruitment and macrophage polarization

In situ mesenchymal stem cells (MSCs) regenerative therapy holds promising potential for treating osteoarthritis. However, MSCs engraftment and intra-articular inflammation limit the therapeutic efficacy of this approach. This study introduces porous microspheres (PMs) composed of aldehyde-modified poly(lactic-co-glycolic acid), that encapsulate platelet derived growth factor-AB and kartogenin. Metformin (Met) is also incorporated onto the microsphere through a Schiff base reaction to create PMs@Met. In vitro, in vivo and ex experiments revealed that PMs@Met can be injected into the joint cavity, effectively recruiting endogenous MSCs in situ. This approach creates a favorable environment for MSCs proliferation. It also controls the intra-articular inflammatory environment by modulating the polarization of synovial macrophages, ultimately promoting cartilage repair. In summary, our study presents an innovative tissue engineering strategy for the treatment of osteoarthritis-induced articular cartilage injuries. Statement of significanceCell therapy using autologous mesenchymal stem cells (MSCs) has potential to slow the progression of osteoarthritis (OA). Nonetheless, there are some disadvantages to adopting in situ MSCs therapy, including difficulties with MSC engraftment into cartilage-deficient regions, the effect of intra-articular inflammation on MSC therapeutic efficacy, and attaining selective chondrogenic MSC differentiation. We created injectable PLGA microspheres (PMs) that were loaded with PDGF-AB and KGN. Metformin was bonded to the surface of microspheres using a Schiff base reaction. The microspheres can recruit intra-articular MSCs and encourage their development into chondrocytes. The microspheres actively modulate the inflammatory joint environment by altering synovial macrophage polarization, thereby supporting MSCs in effective cartilage treatment. To summarize, microspheres hold great potential in the treatment of OA.

α-Ketoglutarate alleviates osteoarthritis by inhibiting ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography–mass spectrometry (LC–MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.

Genistein promotes cartilage repair and inhibits synovial inflammatory response after anterior cruciate ligament transection in rats by regulating the Wnt/β-catenin axis.

To confirm the protective mechanism of genistein on osteoarthritis (OA). Firstly, we constructed an anterior cruciate ligament transection (ACLT) rat model and administered two doses of genistein via gavage. The effects of the drug on cartilage damage repair and synovitis in OA rats were evaluated through pain-related behavioral assessments, pathological staining, detection of inflammatory factors, and western blot analysis. Secondly, we constructed IL-1-induced chondrocytes and synovial fibroblast models, co-incubated them with genistein, and evaluated the protective effects of genistein on both types of cells through cell apoptosis and cytoskeleton staining. To verify the role of this pathway, we applied the GSK3β inhibitor TWS119 and the Wnt/β-catenin inhibitor XAV939 to ACLT rats and two types of cells to analyze the potential mechanism of genistein's action on OA. Our results confirmed the protective effect of genistein on joint cartilage injury in ACLT rats and its alleviating effect on synovitis. The results of cell experiments showed that genistein can protect IL-1β-induced chondrocytes and synovial fibroblasts, inhibit IL-1β-induced cell apoptosis, increase the fluorescence intensity of F-actin, and inhibit inflammatory response. The results of in vivo and in vitro mechanism studies indicated that TWS119 and XAV939 can attenuate the protective effects of genistein on OA rats and IL-1-induced cell damage. Our research confirmed that genistein may be an effective drug for treating osteoarthritis. Furthermore, we discussed and confirmed that the GSK3β/Wnt/β-catenin axis serves as a downstream signaling pathway of genistein, providing theoretical support for its application.

Inflammatory macrophage reprogramming strategy of fucoidan microneedles-mediated ROS-responsive polymers for rheumatoid arthritis

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.