Chondrocyte Function Research Articles

CRNDE alleviates IL-1β-induced chondrocyte damage by modulating miR-31/NF-κB pathway

BackgroundThe long non-coding RNA CRNDE (CRNDE) has been identified as a lncRNA associated with osteoarthritis (OA), playing a role the age-related degeneration of articular cartilage. However, the precise mechanism by which CRNDE affects the physiological functions of OA chondrocytes remains unclear.MethodsTo simulate the inflammatory conditions observed in OA, interleukin (IL)-1β-stimulated chondrocyte C-28/I2 cells were utilized. The expression levels of CRNDE and miR-31 were assessed using reverse transcription-polymerase chain reaction (RT-PCR). Chondrocyte viability and apoptosis were evaluated through CCK-8 assay and flow cytometry, respectively. The levels of IL-6, IL-1β and Tumor necrosis factor (TNF-α) were determined using enzyme-linked immunosorbent assay (ELISA). mRNA expression levels of MMP-13, Aggrecan and COL2A1 were detected by quantitative RT-PCR. Western blot analysis was performed to evaluate the protein levels of factors related to cartilage matrix degradation, including p-p65, p65 and p-IκBα of the NF-κB pathway.ResultsCRNDE expression was downregulated in both OA cartilage tissues and IL-1β-stimulated chondrocytes. Overexpression of CRNDE mitigated IL-1β-stimulated chondrocytes apoptosis, inflammatory responses, and cartilage matrix degradation. Compared with healthy controls, OA tissues exhibited reduced expression of miR-31, which was negatively correlated with the expression of CRNDE. Additionally, overexpression of miR-31 partially reversed the inhibitory effects of CRNDE on apoptosis, inflammation, cartilage matrix degradation, and the inactivation of Nuclear factor (NF)-κB pathway induced by IL-1β stimulation. Moreover, silencing of CRNDE exacerbated IL-1β-induced chondrocytes damage, which was aliviated by the NF-κB pathway inhibitor, Bay 11-7082.ConclusionCRNDE alleviated IL-1β-induced injuries in OA chondrocytes by suppressing the miR-31-mediated NF-κB signaling pathway.

Mechanical Signal Transduction: A Key Role of Fluid Shear Forces in the Development of Osteoarthritis.

Globally, osteoarthritis is a common and highly disabling disease that places a heavy burden on society and medical systems. The role of biomechanical factors in the development of osteoarthritis has gradually received more attention. As a key biomechanical stimulus, fluid shear force is becoming the focus of research for its dual role in maintaining cartilage health and disease progression. This paper conducts an in-depth discussion on the mechanism of fluid shear force in osteoarthritis and its impact on the disease process, aiming to reveal how fluid shear stress affects the development of osteoarthritis by regulating the physiological function and signal transduction pathways of chondrocytes.

TGF-β2 enhances nanoscale cortex stiffness via condensation of cytoskeleton-focal adhesion plaque.

Physical spatiotemporal characteristics of cellular cortex dominate cell functions and even determine cell fate. The cellular cortex is able to re-organize to a dynamic steady status with changed stiffnesses once stimulated, and thus alter the physiological and pathological activities of almost all types of cells. TGF-β2, a potent pleiotropic growth factor, plays important roles in cartilage development, endochondral ossification, and cartilage diseases. However, it is not yet known whether TGF-β2 would alter the physical spatiotemporal characteristics of the cell cortex such as cortex stiffness, thereby affecting the function of chondrocytes. In this study, we investigated the influence of TGF-β2 on cellular cortex stiffness of chondrocytes and the underlying mechanism. We firstly detected TGF-β2-induced changes in cytoskeleton and focal adhesion plaque, which were closely related to cellular cortex stiffness. We then characterized the landscape of nanoscale cortex stiffness in individual chondrocytes induced by TGF-β2 via atomic force microscope (AFM). By using inhibitors, latrunculin A and blebbistatin, we verified the importance of cytoskeleton-focal adhesion plaque axis on cellular cortex stiffness of chondrocytes induced by TGF-β2. We finally elucidated that TGF-β2 enhanced the phosphorylation of Smad3 and facilitated the nuclear accumulation of p-Smad3. The p-Smad3 aggregated in the nuclei enhanced the cytoskeleton and focal adhesion plaque at transcriptional level, thereby mediating changes in cell cortex stiffness. Taken together, these results provide an understanding about the role of TGF-β2 on physical spatiotemporal properties of cell cortex in chondrocytes, and might provide cues for interpretation of cartilage development and interventions to cartilage diseases.

Serinc5 Regulates Sequential Chondrocyte Differentiation by Inhibiting Sox9 Function in Pre-Hypertrophic Chondrocytes.

The growth plate is the primary site of longitudinal bone growth with chondrocytes playing a pivotal role in endochondral bone development. Chondrocytes undergo a series of differentiation steps, resulting in the formation of a unique hierarchical columnar structure comprising round, proliferating, pre-hypertrophic, and hypertrophic chondrocytes. Pre-hypertrophic chondrocytes, which exist in the transitional stage between proliferating and hypertrophic stages, are a critical cell population in the growth plate. However, the molecular basis of pre-hypertrophic chondrocytes remains largely undefined. Here, we employed scRNA-seq analysis on fluorescently labeled growth plate chondrocytes for their molecular characterization. Serine incorporator 5 (Serinc5) was identified as a marker gene for pre-hypertrophic chondrocytes. Histological analysis revealed that Serinc5 is specifically expressed in pre-hypertrophic chondrocytes, overlapping with Indian hedgehog (Ihh). Serinc5 represses cell proliferation and Col2a1 and Acan expression by inhibiting the transcriptional activity of Sox9 in primary chondrocytes. Chromatin profiling using ChIP-seq and ATAC-seq revealed an active enhancer of Serinc5 located in intron 1, with its chromatin status progressively activated during chondrocyte differentiation. Collectively, our findings suggest that Serinc5 regulates sequential chondrocyte differentiation from proliferation to hypertrophy by inhibiting Sox9 function in pre-hypertrophic chondrocytes, providing novel insights into the mechanisms underlying chondrocyte differentiation in growth plates.

Proteoglycans Enhance the Therapeutic Effect of BMSC Transplantation on Osteoarthritis.

The injection of bone mesenchymal stem cells (BMSCs) for osteoarthritis (OA) treatment fails to address the disrupted extracellular microenvironment, limiting the differentiation and paracrine functions of BMSCs and resulting in suboptimal therapeutic outcomes. Proteoglycans (PGs) promote cell differentiation, tissue repair, and microenvironment remodeling. This study investigated the potential of combining PGs with BMSCs to increase the efficacy of OA treatment. We evaluated the effects of PG on BMSC and chondrocyte functions by adding various PG concentrations to the culture media. Additionally, a Transwell system was used to assess the impact of PG on the communication between BMSCs and chondrocytes. The results of the in vitro experiment were verified by tissue staining and immunohistochemistry following the treatment of OA model rats. Our findings indicate that PG effectively induces Col II expression in BMSCs and enhances the paracrine secretion of TGF-β1, thereby activating the TGF-β signaling pathway in chondrocytes and increasing PRG4 gene expression. Compared with the other groups, the BMSC/PG treatment group presented a smoother articular surface and more robust extracellular matrix than the other groups in vivo, with significantly increased expression and distribution of Smad2/3 and PRG4. PG enhances BMSC differentiation into chondrocytes and stimulates paracrine TGF-β1 secretion. Proteoglycans not only promote chondrocyte differentiation and paracrine TGF-β1 signaling in BMSCs but also increase the sensitivity of chondrocytes to TGF-β1 secreted from BMSCs, leading to PRG4 expression through the TGFR/Smad2/3 pathway. Proteoglycans can enhance the therapeutic effect of BMSC treatment on OA and have the potential to delay the degeneration of OA cartilage.

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.

The Role of Cartilage Tissue Engineering in Osteoarthritis Treatment: The Bench to Bedside Translation

ABSTRACTCartilage tissue engineering holds huge promise for joint defects and osteoarthritis (OA) conditions which otherwise have limited treatment options due to cartilage's inherent inability to self‐repair. Chemical cues play a pivotal role in regulating chondrocyte behavior and matrix synthesis. Strategies utilizing growth factors, small molecules, and biomaterial‐based delivery systems aim to modulate chondrogenic differentiation, proliferation, and matrix deposition, while recent insights emphasize the significance of mimicking native tissue gradients for optimal regeneration outcomes. Mechanical stimuli profoundly influence chondrocyte phenotype and function, necessitating precise control of the mechanical microenvironment in tissue engineering strategies. Advances in biomaterial design, scaffold fabrication, and bioreactor systems facilitate the tailored modulation of mechanical cues, including substrate stiffness, topography, and dynamic loading regimes. This review showcases the latest advancements in engineering both the chemical and mechanical microenvironment to enhance chondrocyte regeneration. Furthermore, exploring the synergistic effects of combining chemical and mechanical cues underscores the importance of multifaceted approaches in promoting robust chondrocyte regeneration. The review also addresses challenges and future directions in the field, such as achieving spatially organized tissue architecture and integrating patient‐specific factors, to propel advancements in cartilage tissue engineering. We also conducted a comprehensive enlistment for the clinical trials and tissue engineering‐based marketed products for OA therapy.

Carbonic anhydrase 2 is important for articular chondrocyte function and metabolic homeostasis

ObjectivesAberrant chondrocyte metabolism significantly contributes to cartilage degeneration and osteoarthritis (OA) genesis. However, the mechanisms driving the metabolic shift in OA chondrocytes remain unclear. Interestingly, carbonic anhydrase 2 (CA2) is implicated in metabolic regulation, and its expression dramatically increases in OA chondrocytes, but its exact role and mechanism are poorly understood. This study investigates the mechanistic role of CA2 in chondrocyte metabolic homeostasis under hypoxic and inflammatory conditions. MethodsRNA-seq was performed on CA2-deficient C28/I2 cells to identify pathways affected by the loss of CA2 function. We examined CA2’s impact on chondrocyte metabolism, anabolism, and catabolism using C28/I2 cells and primary chondrocytes under normoxia and hypoxia and in a model of inflammatory OA. ResultsRNA-seq revealed enrichment of glycolysis, apoptosis, and TNF signaling pathways in CA2-deficient cells. Under hypoxia, CA2 expression increased 10-fold in a HIF-1α-independent manner. Knockdown of CA2 reduced extracellular lactate production, increased ADP/ATP ratio, impaired glycolysis, reduced glycolytic capacity, and lowered expression of glycolysis rate-limiting enzymes but did not disrupt pHi and ROS production. CA2 deficiency altered chondrocyte anabolic and catabolic equilibrium by affecting PI3K/AKT and RELA/p65 signaling. CA2-deficient chondrocytes displayed impeded migration, suppressed proliferation, and cell cycle arrest at the G0/G1 phase. Forced expression of CA2 stabilized chondrocyte metabolism and restored cellular functions. ConclusionsOur research uncovered a hitherto unknown mechanistic role for CA2 in regulating chondrocyte energy metabolism and inflammation, underscoring its potential as a critical mediator in OA pathogenesis. Further research using a murine model of experimental OA is warranted to capture the functional implications of CA2.

Chondrocyte autophagy mechanism and therapeutic prospects in osteoarthritis.

Osteoarthritis (OA) is the most common type of arthritis characterized by progressive cartilage degradation, with its pathogenesis closely related to chondrocyte autophagy. Chondrocytes are the only cells in articular cartilage, and the function of chondrocytes plays a vital role in maintaining articular cartilage homeostasis. Autophagy, an intracellular degradation system that regulates energy metabolism in cells, plays an incredibly important role in OA. During the early stages of OA, autophagy is enhanced in chondrocytes, acting as an adaptive mechanism to protect them from various environmental changes. However, with the progress of OA, chondrocyte autophagy gradually decreases, leading to the accumulation of damaged organelles and macromolecules within the cell, prompting chondrocyte apoptosis. Numerous studies have shown that cartilage degradation is influenced by the senescence and apoptosis of chondrocytes, which are associated with reduced autophagy. The relationship between autophagy, senescence, and apoptosis is complex. While autophagy is generally believed to inhibit cellular senescence and apoptosis to promote cell survival, recent studies have shown that some proteins are degraded by selective autophagy, leading to the secretion of the senescence-associated secretory phenotype (SASP) or increased SA-β-Gal activity in senescent cells within the damaged region of human OA cartilage. Autophagy activation may lead to different outcomes depending on the timing, duration, or type of its activation. Thus, our study explored the complex relationship between chondrocyte autophagy and OA, as well as the related regulatory molecules and signaling pathways, providing new insights for the future development of safe and effective drugs targeting chondrocyte autophagy to improve OA.

A single-cell 3D dynamic volume control system for chondrocytes.

In articular cartilage, zone-specific cellular morphology is a typical characteristic of cartilage tissue, which is related with chondrocyte function, inflammation and osteoarthritis (OA). Chondrocyte hypertrophic phenotype is a criticle physiological process which indicates a hallmark of chondrocyte terminal differentiation and bone formation. Thus, developing a in vitro cell culture system for dynamic regulation of single chondrocyte volume at a three-dimensional (3D) level is particularly necessary for understanding how physical cues of matrix microenvironment regulate chondrocyte fate and the degeneration of articular cartilage. Here, based on the soft lithography techniques, we have constructed well-defined single-cell 3D dynamic volume control system to recapitulate the physiological matrix microenvironment of single chondrocyte niche. The results of finite element analysis indicated that the stress and strain distribution in the cell culture region is homogeneous during the stretching process. Additionally, 3D dynamic volume expansion and compression of single cells in physiological or hyperphysiological can be realized in this cell culture system. Our device for single-cell 3D dynamic culture provides a microphysiological culture system for chondrocytes to explore the mechanisms of cartilage hypertrophy, as well as develops a new paradigm for functional cartilage tissue engineering and regenerative medicine.

Interplay of Glucose Metabolism and Hippo Pathway in Chondrocytes: Pathophysiology and Therapeutic Targets.

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA.

Matrix Viscoelasticity Tunes the Mechanobiological Behavior of Chondrocytes.

In articular cartilage, the pericellular matrix acting as a specialized mechanical microenvironment modulates environmental signals to chondrocytes through mechanotransduction. Matrix viscoelastic alterations during cartilage development and osteoarthritis (OA) degeneration play an important role in regulating chondrocyte fate and cartilage matrix homeostasis. In recent years, scientists are gradually realizing the importance of matrix viscoelasticity in regulating chondrocyte function and phenotype. Notably, this is an emerging field, and this review summarizes the existing literatures to the best of our knowledge. This review provides an overview of the viscoelastic properties of hydrogels and the role of matrix viscoelasticity in directing chondrocyte behavior. In this review, we elaborated the mechanotransuction mechanisms by which cells sense and respond to the viscoelastic environment and also discussed the underlying signaling pathways. Moreover, emerging insights into the role of matrix viscoelasticity in regulating chondrocyte function and cartilage formation shed light into designing cell-instructive biomaterial. We also describe the potential use of viscoelastic biomaterials in cartilage tissue engineering and regenerative medicine. Future perspectives on mechanobiological comprehension of the viscoelastic behaviors involved in tissue homeostasis, cellular responses, and biomaterial design are highlighted. Finally, this review also highlights recent strategies utilizing viscoelastic hydrogels for designing cartilage-on-a-chip.

In-situ hydrogen-generating injectable short fibers for osteoarthritis treatment by alleviating oxidative stress

Hydrogen (H₂) has great potential in the treatment of osteoarthritis, but its rapid diffusion and short retention time make it difficult to exert stable therapeutic effects. This study developed a short-fiber injectable material that can continuously generate hydrogen in situ to eliminate reactive oxygen species (ROS), alleviate oxidative stress and inflammation, and promote tissue repair. We prepared H–Si nanosheets with high hydrogen generation efficiency using a wet chemical exfoliation method and combined them with GelMA short fibers via electrospinning technology, achieving the in situ delivery of H–Si nanosheets and regulated hydrogen generation rate through the encapsulation and degradation of GelMA, ultimately achieving continuous and controlled hydrogen supply and stable therapeutic effects for osteoarthritis. In vitro and in vivo experiments confirmed the safety and efficacy of this material. The results showed that the material could continuously and efficiently generate hydrogen in simulated physiological environments (100 mg of material could generate 8.6 % hydrogen), effectively eliminate cellular reactive oxygen species (ROS positive rate reduced by 85.89 %), reduce cellular senescence and apoptosis (cell death rate decreased by 52 %, SA-βgal expression decreased by 78.3 %), promote normal chondrocyte function (Col II expression increased by 67.4 %, Ki67 expression increased by 87.5 %), and improve osteoarthritis in rats (OARSI score increased by 216 %). The in situ hydrogen generation and control system designed in this study provides a new method for the hydrogen's local and stable treatment of osteoarthritis. Statement of significanceHydrogen (H₂) has great potential in the treatment of osteoarthritis by alleviating oxidative stress, but its rapid diffusion and short retention time make it difficult to exert stable therapeutic effects. This study introduces an innovative injectable material combining H–Si nanosheets and GelMA short fibers to address this issue. By enabling continuous in situ hydrogen generation, this material effectively eliminates reactive oxygen species, reduces oxidative stress and inflammation, and promotes tissue repair. In vitro and in vivo experiments demonstrate its high hydrogen generation efficiency, safety, and therapeutic efficacy, offering a promising new approach for osteoarthritis management.

Supramolecular nanoparticle loaded with bilirubin enhances cartilage protection and alleviates osteoarthritis via modulating oxidative stress and inflammatory responses

Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by β-cyclodextrin (β-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-β-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.

Catabolic mediators from TLR2-mediated proteoglycan aggrecan peptide-stimulated chondrocytes are reduced by Lactobacillus-conditioned media

In osteoarthritis (OA), extracellular matrix (ECM) digestion by cartilage-degrading enzymes drives cartilage destruction and generates ECM fragments, such as proteoglycan aggrecan (PG) peptides. PG peptides have been shown to induce immunological functions of chondrocytes. However, the role of PG peptides in stimulating catabolic mediators from chondrocytes has not been investigated. Therefore, we aim to determine the effects and its mechanism by which PG peptides induce chondrocytes to produce catabolic mediators in OA. Human chondrocytes were stimulated with IFNγ and various PG peptides either (i) with or (ii) without TLR2 blockade or (iii) with Lactobacillus species-conditioned medium (LCM), a genus of bacteria with anti-inflammatory properties. Transcriptomic analysis, cartilage-degrading enzyme production and TLR2-intracellular signaling activation were investigated. Chondrocytes treated with PG peptides p16-31 and p263-280 increased expression levels of genes associated with chondrocyte hypertrophy, cartilage degradation and proteolytic enzyme production. TLR2 downstream signaling proteins (STAT3, IkBα and MAPK9) were significantly phosphorylated in p263-280 peptide-stimulated chondrocytes. MMP-1 and ADAMTS-4 were significantly reduced in p263-280 peptides-treated condition with TLR2 blockade or LCM treatment. Phosphorylation levels of IkBa, ERK1/2 and MAPK9 were significantly decreased with TLR2 blockade, but only phosphorylation levels of MAPK9 was significantly decreased with LCM treatment. Our study showed that PG peptide stimulation via TLR2 induced cartilage-degrading enzyme production via activation of MAPK, NFκB and STAT3 pathways.

Lubricin-Inspired Nanozymes Reconstruct Cartilage Lubrication System with an "In-Out" Strategy.

Lubricin, secreted primarily by chondrocytes, plays a critical role in maintaining the function of the cartilage lubrication system. However, both external factors such as friction and internal factors like oxidative stress can disrupt this system, leading to osteoarthritis. Inspired by lubricin, a lubricating nanozyme, that is, Poly-2-acrylamide-2-methylpropanesulfonic acid sodium salt-grafted aminofullerene, is developed to restore the cartilage lubrication system using an "In-Out" strategy. The "Out" aspect involves reducing friction through a combination of hydration lubrication and ball-bearing lubrication. Simultaneously, the "In" aspect aims to mitigate oxidative stress by reducing free radical, increasing autophagy, and improving the mitochondrial respiratory chain. This results in reduced chondrocyte senescence and increased lubricin production, enhancing the natural lubrication ability of cartilage. Transcriptome sequencing and Western blot results demonstrate that it enhances the functionality of mitochondrial respiratory chain complexes I, III, and V, thereby improving mitochondrial function in chondrocytes. In vitro and in vivo experiments show that the lubricating nanozymes reduce cartilage wear, improve chondrocyte senescence, and mitigate oxidative stress damage, thereby mitigating the progression of osteoarthritis. These findings provide novel insights into treating diseases associated with oxidative stress and frictional damage, such as osteoarthritis, and set the stage for future research and development of therapeutic interventions.

The emerging role of the semaphorin family in cartilage and osteoarthritis.

In the pathogenesis of osteoarthritis, various signaling pathways may influence the bone joint through a common terminal pathway, thereby contributing to the pathological remodeling of the joint. Semaphorins (SEMAs) are cell-surface proteins actively involved in and primarily responsible for regulating chondrocyte function in the pathophysiological process of osteoarthritis (OA). The significance of the SEMA family in OA is increasingly acknowledged as pivotal. This review aims to summarize the mechanisms through which different members of the SEMA family impact various structures within joints. The findings indicate that SEMA3A and SEMA4D are particularly relevant to OA, as they participate in cartilage injury, subchondral bone remodeling, or synovitis. Additionally, other elements such as SEMA4A and SEMA5A may also contribute to the onset and progression of OA by affecting different components of the bone and joint. The mentioned mechanisms demonstrate the indispensable role of SEMA family members in OA, although the detailed mechanisms still require further exploration.

Obesity, Metabolic Syndrome, and Osteoarthritis Require Integrative Understanding and Management.

Osteoarthritis (OA) is a progressive chronic disease affecting the articular joints, leading to pain and disability. Unlike traditional views that primarily link OA to aging, recent understanding portrays it as a multifactorial degenerative disease of the entire joint. Emerging research highlights metabolic and immune dysregulation in OA pathogenesis, emphasizing the roles of obesity, dyslipidemia, and insulin resistance in altering joint homeostasis. Recent studies have increasingly focused on the complex role of white adipose tissue (WAT) in OA. WAT not only serves metabolic functions but also plays a critical role in systemic inflammation through the release of various adipokines. These adipokines, including leptin and adiponectin, have been implicated in exacerbating cartilage erosion and promoting inflammatory pathways within joint tissues. The overlapping global crises of obesity and metabolic syndrome have significantly impacted joint health. Obesity, now understood to contribute to mechanical joint overload and metabolic dysregulation, heightens the risk of developing OA, particularly in the knee. Metabolic syndrome compounds these risks by inducing chronic inflammation and altering macrophage activity within the joints. The multifaceted effects of obesity and metabolic syndrome extend beyond simple joint loading. These conditions disrupt normal joint function by modifying tissue composition, promoting inflammatory macrophage polarization, and impairing chondrocyte metabolism. These changes contribute to OA progression, highlighting the need for targeted therapeutic strategies that address both the mechanical and biochemical aspects of the disease. Recent advances in understanding the molecular pathways involved in OA suggest potential therapeutic targets. Interventions that modulate macrophage polarization, improve chondrocyte function, or normalize adipokine levels could serve as preventative or disease-modifying therapies. Exploring the role of diet, exercise, and pharmacological interventions in modulating these pathways offers promising avenues for reducing the burden of OA. Furthermore, such methods could prove cost-effective, avoiding the increase in access to healthcare.

Melatonin ameliorates Slc26a2-associated chondrodysplasias by attenuating endoplasmic reticulum stress and apoptosis of chondrocytes

Although the pathogenesis and mechanism of congenital skeletal dysplasia are better understood, progress in drug development and intervention research remains limited. Here we report that melatonin treatment elicits a mitigating effect on skeletal abnormalities caused by SLC26A2 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon SLC26A2 deficiency, we found calcium (Ca2+) overload jointly contributed to SLC26A2-associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca2+ overload in turn triggered apoptosis of growth plate chondrocytes. Melatonin, known for its anti-oxidant and anti-inflammatory properties, emerged as a promising therapeutic approach in our study, which enhanced survival, proliferation, and maturation of chondrocytes by attenuating endoplasmic reticulum stress and Ca2+ overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of SLC26A2-deficient chondrocytes in vitro but also underscored its role in partially alleviating the skeletal dysplasia seen in Col2a1-CreERT2; Slc26a2fl/fl mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum in vivo. Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for SLC26A2-related chondrodysplasias.

MiR-653-5p drives osteoarthritis pathogenesis by modulating chondrocyte senescence

BackgroundDue to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression.MethodsWe screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus.ResultsMiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice.ConclusionsMiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.