Cartilage Degradation Research Articles

From Inflammation to Resolution: Specialized Pro-resolving Mediators in Posttraumatic Osteoarthritis.

To provide a comprehensive overview of the inflammatory response following anterior cruciate ligament (ACL) injury and to highlight the relationship between specialized pro-resolving mediators (SPMs) and inflammatory joint conditions, emphasizing the therapeutic potential of modulating the post-injury resolution of inflammation to prevent posttraumatic osteoarthritis (PTOA). The inflammatory response triggered after joint injuries such as ACL tear plays a critical role in posttraumatic osteoarthritis development. Inflammation is a necessary process for tissue healing, but unresolved or overactivated inflammation can lead to chronic diseases. SPMs, a family of lipid molecules derived from essential fatty acids, have emerged as active players in the resolution of inflammation and tissue repair. While their role in other inflammatory conditions has been studied, their relationship with PTOA remains underexplored. Proinflammatory mediators contribute to cartilage degradation and PTOA pathogenesis, while anti-inflammatory and pro-resolving mediators may have chondroprotective effects. Therapies aimed at suppressing inflammation in PTOA have limitations, as inflammation is crucial for tissue healing. SPMs offer a pro-resolving response without causing immunosuppression, making them a promising therapeutic option. The known onset date of PTOA makes it amenable to early interventions, and activating pro-resolving pathways may provide new possibilities for preventing PTOA progression. Harnessing the pro-resolving potential of SPMs may hold promise for preventing PTOA and restoring tissue homeostasis and function after joint injuries.

Exploring the Feasibility of Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Osteoarthritis: Challenges and Opportunities.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage degradation and joint inflammation. As the most common aging-related joint disease, OA is marked by inadequate extracellular matrix synthesis and the breakdown of articular cartilage. However, traditional diagnostic methods for OA, relying on clinical assessments and radiographic imaging, often need to catch up in detecting early-stage disease or i accurately predicting its progression. Consequently, there is a growing interest in identifying reliable biomarkers that can facilitate early diagnosis and prognosis of OA. MicroRNAs (miRNAs) have emerged as potential candidates due to their involvement in various cellular processes, including cartilage homeostasis and inflammation. This review explores the feasibility of circulating miRNAs as diagnostic and prognostic biomarkers in OA, focusing on knee OA while shedding light on the challenges and opportunities associated with their implementation in clinical practice.

Pyroptosis of chondrocytes activated by synovial inflammation accelerates TMJ osteoarthritis cartilage degeneration via ROS/NLRP3 signaling

ObjectivesSynovial inflammation and chondrocyte death have been widely acknowledged as key contributors to the pathological progression of temporomandibular joint osteoarthritis (TMJ-OA), a degenerative joint disease currently lacking definitive treatments. This study aims to understand the regulatory role of chondrocyte pyroptosis in condylar cartilage degradation during TMJ-OA. MethodsThe levels of cytokines, cartilage degeneration markers, and pyroptotic biomarkers in the synovium and synovial fluid of temporomandibular disorders (TMD) patients were examined. The synovitis, cartilage degradation, and chondrocyte pyroptosis in wild-type and alpha-kinase 1 (ALPK1)-deficient TMJ-OA mice were then compared following monosodium iodoacetate (MIA) induction. Subsequently, we investigated the downstream mechanisms of cytokines- or macrophage supernatants-induced metabolic disorders and pyroptosis in chondrocytes using primary TMJ chondrocytes and ATDC5 chondrocyte cultures. ResultsWe found a positive correlation between pyroptotic biomarkers and cartilage degradation mediators and cytokines in the synovial fluid of TMD patients. MIA-induced TMJ-OA mice demonstrated significant synovitis, cartilage degradation, and chondrocyte pyroptosis, which were mitigated in ALPK1-deficient TMJ-OA mice, inflammation-restrained mice. Ex-vivo study revealed the contribution of reactive oxygen species (ROS) to inflammation-irritated macrophage supernatants-induced pyroptosis and metabolic disorders in chondrocytes. Targeting NOD-like receptor protein 3 (NLRP3) alleviated cytokines- or ROS-induced pyroptosis and metabolic disorders in chondrocytes by inhibiting caspase-1 activation and interleukin-1β (IL-1β) secretion. ConclusionOur findings offer novel insight into the role of synovial inflammation-induced chondrocyte pyroptosis in promoting cartilage degradation during TMJ-OA via the ROS and NLRP3 signaling pathway.

Efektifitas Knee Pain Exercise Dan Kompres Hangat Terhadap Nyeri Osteoarthritis Lutut Di Desa Mojolegi Kecamatan Gading Kabupaten Probolingg0

Osteoarthritis of the knee in the elderly can cause pain due to the degradation of joint cartilage in which the joint cartilage is damaged which is characterized by changes in the joint capsule and damage to the cartilage located at the bone joints. Knee Pain Exercise and warm compresses are two methods that can be used to manage knee osteoarthritis pain.. The purpose of this study was to analyze the effectiveness of knee pain exercise and warm compresses on reducing knee osteoarthritis pain in the elderly. Using a purposive sampling technique, a sample of 40 respondents was drawn from the population of up to 125 people. A cross-over group design technique and a quasi-experimental approach were used in the research design. The instrument used was a Numeric Rating Scale (NRS) observation sheet. The normality of the data was tested using the Kolmogorov-Smirnov. The hypotheses were tested and analyzed using paired samples T test with p-value 0.000 on each variable which means that there is an effect of knee pain exercise and warm compresses on knee osteoarthritis pain. The effectiveness test used independent samples test and it was found that warm compresses had the smallest mean value (2.55), which means that warm compresses were more effective in reducing knee osteoarthritis pain than knee pain exercise. It is expected that the elderly who experience knee osteoarthritis pain do regular exercise which is a physical exercise to reduce knee osteoarthritis pain.
 

Biomimetic approach for an articular cartilage patch: Combination of decellularized cartilage matrix and silk-elastin-like-protein (SELP) hydrogel

Articular cartilage degradation due to injury, disease and aging is a common clinical issue as current regenerative therapies are unable to fully replicate the complex microenvironment of the native tissue which, being avascular, is featured by very low ability to self-regenerate. The extracellular matrix (ECM), constituting almost 90% of the entire tissue, plays a critical role in its function and resistance to compressive forces. In this context, the current tissue engineering strategies are only partially effective in restoring the biology and function of the native tissue. A main issue in tissue regeneration is treatment failure due to scarce integration of the engineered construct, often following a gradual detachment of the graft. In this scenario, we aimed to create an adhesive patch able to adequately support cartilage regeneration as a promising tool for the treatment of cartilage injuries and diseases. For this, we produced an engineered construct composed of decellularized ECM (dECM) obtained from horse joint cartilage, to support tissue regeneration, coupled with a Silk-Elastin-Like Proteins (SELP) hydrogel, which acts as a biological glue, to guarantee an adequate adherence to the host tissue. Following the production of the two biomaterials we characterized them by assessing: 1) dECM morphological, chemical, and ultrastructural features along with its capability to support chondrocyte proliferation, specific marker expression and ECM synthesis; 2) SELP microarchitecture, cytocompatibility and mechanical properties. Our results demonstrated that both materials hold unique properties suitable to be exploited to produce a tailored microenvironment to support cell growth and differentiation providing a proof of concept concerning the in vitro biological and mechanical efficacy of the construct. The SELP hydrogel displayed a very interesting physical behavior due to its high degree of resistance to mechanical stress, which is generally associated with physiological mechanical load during locomotion. Intriguingly, the shear-thinning behavior of the hydrogel may also make it suitable to be applied and spread over non-homogeneous surfaces, therefore, we hypothesize that the hybrid biomaterial proposed may be a real asset in the treatment of cartilage defects and injuries.

Rehmannia alcohol extract inhibits neuropeptide secretion and alleviates osteoarthritis pain through cartilage protection

Osteoarthritis (OA) is a common joint disease characterized by chronic pain, and the perception of pain is closely associated with brain function and neuropeptide regulation. Rehmannia is common plant herb with anti-inflammatory and analgesic properties that is used to treat OA. However, it is unclear whether Rehmannia alleviates OA-related pain via regulation of neuropeptides and brain function. We examined the pain relief regulatory pathway in OA after treatment with Rehmannia by verifying the therapeutic effect of Rehmannia alcohol extract in vivo and vitro and exploring of the potential mechanism underlying the analgesic effect of Rahmanian using functional magnetic resonance imaging and measuring neuropeptide secretion. Our results showed that Rehmannia alcohol extract and the related active ingredient, Rehmannioside D, can delay cartilage degradation and alleviate inflammation in OA rats. The Rehmannia alcohol extract can also relieve OA pain, reduce the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP), and reverse the pathological changes in the cerebral cortex and hippocampus. Our research results demonstrate that Rehmannia alleviates OA pain by protecting cartilage, preventing the stimulation of inflammatory factors on neuropeptide secretion, and influencing the relevant functional areas of the brain.

Rheumatoid arthritis molecular targets and their importance to flavonoid-based therapy.

Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.

Low-frequency whole-body vibration can enhance cartilage degradation with slight changes in subchondral bone in mice with knee osteoarthritis and does not have any morphologic effect on normal joints.

To evaluate the effects of low frequency whole-body vibration (WBV) on degeneration of articular cartilage and subchondral bone in mice with destabilization of the medial meniscus (DMM)induced osteoarthritis(OA) and mice with normal knee. Ten-week-old C57BL/6J male mice received DMM on right knees, while the left knees performed sham operation. There were six groups: DMM, SHAM DMM, DMM+WBV,SHAM DMM+WBV, DMM+ NON-WBV and SHAM DMM+NON-WBV. After four weeks, the knees were harvested from the DMM and SHAM DMM group. The remaining groups were treated with WBV (10 Hz) or NON-WBV. Four weeks later, the knees were harvested. Genes, containing Aggrecan(Acan) and CollagenⅡ(Col2a1), Matrix Metalloproteinases 3 and 13(MMP3,13), TNFα and IL6, were measured and staining was also performed. OA was graded with OARSI scores, and tibial plateaubone volume to tissue volume ratio(BV/TV), bone surface area to bone volume ratio (BS/BV), trabecular number(Tb.N) and trabecular thickness separation(TS) between groups were analyzed. Increased OARSI scores and cartilage degradation were observed after WBV. BV/TV, Tb.N and TS were not significant between the groups. Significant reductions were observed in MMP3, MMP13, Col2a1, Acan, TNFα and IL6 in the DMM+WBV compared to SHAM DMM+WBV group. BV/TV, BS/BV, Tb.N, TS and OARSI scores were not significantly changed in the left knees. IL6 expression in the SHAM DMM+WBV group was significantly increased compared with the SHAM DMM+ NON-WBV group, while Col2a1, Acan and MMP13 expression decreased. WBV accelerated cartilage degeneration and caused slight changes in subchondral bone in a DMM-induced OA model. WBV had no morphologic effect on normal joints.

Oral Administration of Protease-Soluble Chicken Type II Collagen Ameliorates Anterior Cruciate Ligament Transection-Induced Osteoarthritis in Rats.

This study investigated whether oral supplementation with protease-soluble chicken type II collagen (PSCC-II) mitigates the progression of anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) in rats. Eight-week-old male Wistar rats were randomly assigned to the following groups: control, sham, ACLT, group A (ACLT + pepsin-soluble collagen type II collagen (C-II) with type I collagen), group B (ACLT + Amano M-soluble C-II with type I collagen), group C (ACLT + high-dose Amano M-soluble C-II with type I collagen), and group D (ACLT + unproteolyzed C-II). Various methods were employed to analyze the knee joint: nociceptive tests, microcomputed tomography, histopathology, and immunohistochemistry. Rats treated with any form of C-II had significant reductions in pain sensitivity and cartilage degradation. Groups that received PSCC-II treatment effectively mitigated the ACLT-induced effects of OA concerning cancellous bone volume, trabecular number, and trabecular separation compared with the ACLT alone group. Furthermore, PSCC-II and unproteolyzed C-II suppressed ACLT-induced effects, such as the downregulation of C-II and upregulation of matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1β. These results indicate that PSCC-II treatment retains the protective effects of traditional undenatured C-II and provide superior benefits for OA management. These benefits encompass pain relief, anti-inflammatory effects, and the protection of cartilage and cancellous bone.

Adseverin, an actin-binding protein, modulates hypertrophic chondrocyte differentiation and osteoarthritis progression.

In osteoarthritis (OA), a disease characterized by progressive articular cartilage degradation and calcification, the articular chondrocyte phenotype changes and this correlates with actin cytoskeleton alterations suggesting that it regulates gene expression essential for proper phenotype. This study reports that OA is associated with the loss of adseverin, an actin capping and severing protein. Adseverin deletion (Adseverin-/-) in mice compromised articular chondrocyte function, by reducing F-actin and aggrecan expression and increasing apoptosis, Indian hedgehog, Runx2, MMP13, and collagen type X expression, and cell proliferation. This led to stiffer cartilage and decreased hyaline and increased calcified cartilage thickness. Together, these changes predisposed the articular cartilage to enhanced OA severity in Adseverin-/- mice who underwent surgical induction of OA. Adseverin-/- chondrocyte RNA sequencing and in vitro studies together suggests that adseverin modulates cell viability and prevents mineralization. Thus, adseverin maintains articular chondrocyte phenotype and cartilage tissue homeostasis by preventing progression to hypertrophic differentiation in vivo. Adseverin may be chondroprotective and a potential therapeutic target.

Acupotomy ameliorates subchondral bone absorption and mechanical properties in rabbits with knee osteoarthritis by regulating bone morphogenetic protein 2-Smad1 pathway.

To investigate the effects of acupotomy on the subchondral bone absorption and mechanical properties in rabbits with knee osteoarthritis (KOA). The rabbits were divided into blank control, model, acupotomy and electroacupuncture (EA) groups, with 12 rabbits in each. Modified Videman's method was used to prepare KOA model. The acupotomy and EA group were given indicated intervention for 3 weeks. The behavior of rabbits in each group was recorded. Subsequently, cartilage-subchondral bone units were obtained and morphological changes were observed by optical microscope and micro computed tomography. Compression test was used to detect the mechanical properties of subchondral bone, Western blot and real-time polymerase chain reaction (RT-PCR) were applied to detect the expression of bone morphogenetic protein 2-Smad1 (BMP2-Smad1) pathway in subchondral bone. Compared with the control group, rabbits in the KOA group showed lameness, knee pain, and cartilage degradation; the subchondral bone showed active resorption, the mechanical properties decreased significantly and the BMP2-Smad1 pathway downregulated significantly. Both acupotomy and EA intervention could increase the thickness of trabecular bone (Tb. Th), the bone volume fraction (BV/TV) and the thickness of subchondral bone plate, reduce the separation of trabecular bone (Tb. Sp), improve the maximum load and elastic modulus of subchondral bone, and effectively delay cartilage degeneration in KOA rabbits. This process may be achieved through upregulation the related proteins of BMP2-Smad1 pathway. The maximum load and elastic modulus of subchondral bone in the acupotomy group were slightly better than those in the EA group. Acupotomy could effectively protect cartilage by inhibiting abnormal bone resorption and improving mechanical properties of subchondral bone thorough the related proteins of BMP2-Smad1 pathway in KOA rabbits.

Primary cilium-mediated mechanotransduction in cartilage chondrocytes.

Osteoarthritis (OA) is one of the most prevalent joint disorders associated with the degradation of articular cartilage and an abnormal mechanical microenvironment. Mechanical stimuli, including compression, shear stress, stretching strain, osmotic challenge, and the physical properties of the matrix microenvironment, play pivotal roles in the tissue homeostasis of articular cartilage. The primary cilium, as a mechanosensory and chemosensory organelle, is important for detecting and transmitting both mechanical and biochemical signals in chondrocytes within the matrix microenvironment. Growing evidence indicates that primary cilia are critical for chondrocytes signaling transduction and the matrix homeostasis of articular cartilage. Furthermore, the ability of primary cilium to regulate cellular signaling is dynamic and dependent on the cellular matrix microenvironment. In the current review, we aim to elucidate the key mechanisms by which primary cilia mediate chondrocytes sensing and responding to the matrix mechanical microenvironment. This might have potential therapeutic applications in injuries and OA-associated degeneration of articular cartilage.

Ginkgolide K delays the progression of osteoarthritis by regulating YAP to promote the formation of cartilage extracellular matrix.

Osteoarthritis (OA) is a degenerative disease characterized by cartilage wear and degradation. Ginkgolide K (GK) is a natural compound extracted from Ginkgo biloba leaves and possesses anti-inflammatory and anti-apoptotic effects. We found that the biological characteristics of GK were highly consistent with those of OA medications. This study aimed to determine and verify the therapeutic effect of GK on OA and mechanism of its therapeutic effect. For the in vivo experiment, OA rats were regularly injected in the articular cavity with GK, and the curative effects were observed after 4 and 8 weeks. For the in vitro experiment, we treated OA chondrocytes with different concentrations of GK and then detected the related indices of OA. Through the in vivo and in vitro experiments, we found that GK could promote the production of major components of the cartilage extracellular matrix. Transcriptome sequencing revealed that GK may activate hypoxia-inducible factor 1 alpha via the hypoxia signaling pathway, which, in turn, activates yes-associated protein and inhibits apoptosis of OA chondrocytes. GK has a therapeutic effect on OA and, therefore, has the potential to be developed into a new drug for OA treatment.

ROR1/STAT3 positive feedback loop facilitates cartilage degeneration in Osteoarthritis through activation of NF-κB signaling pathway.

Osteoarthritis (OA) is a chronic joint disorder with a serious impact on society. The main pathological change in OA is articular cartilage degeneration, which is directly associated with imbalance of anabolic and catabolic activities in chondrocytes. To evaluate the expression and biological effects of ROR1 in OA cartilage and determine whether knockdown of ROR1 attenuates cartilage degeneration. ROR1 expression in OA clinical specimens was evaluated by western blotting and immunohistochemistry. The effects of ROR1 on anabolic and catabolic activities were evaluated in Wnt5a-treated human primary chondrocytes by western blotting, immunofluorescence, and luciferase assay. The effects of ROR1 knockdown on cartilage degeneration in a surgical OA mouse model were examined by X-ray imaging and Safranin O-Fast Green histological staining. ROR1 was considerably upregulated in cartilage tissues of OA patients. ROR1 knockdown alleviated the activation of the NF-κB signaling pathway and reversed the suppression of collagen II and aggrecan by Wnt5a, as well as upregulation of ADAMTS-5 and MMP-13 in chondrocytes. In addition, ROR1 knockdown significantly reduced Wnt5a-induced STAT3 nuclear translocation. STAT3 binding to the ROR1 promoter indicated a positive feedback loop between ROR1 and STAT3. ROR1 knockdown was confirmed to dramatically alleviate cartilage degradation in the DMM induced-OA mouse model. Increased expression of ROR1 in OA cartilage tissues leads to a positive feedback loop with STAT3, which activates the NF-κB signaling pathway, resulting in an imbalance between chondrocyte anabolism and catabolism. These results indicate a potential new therapeutic target for the treatment of OA.

Diagnostic value and immune infiltration characterization of YTHDF2 as a critical m6A regulator in osteoarthritic synovitis

BackgroundN6-methyladenosine (m6A) is a universal RNA modification pattern regulated by multiple m6A regulators. In osteoarthritis (OA), m6A regulators influence disease progression by regulating cartilage degradation. However, the function of m6A regulators in synovial tissue remains unclear. In this work, we investigated the biological significance of m6A regulators in osteoarthritic synovitis.MethodsDatasets were acquired from Gene Expression Omnibus. Differential analysis of merged data identified the differentially expressed m6A regulators. Machine learning models were used to evaluate genetic importance. To predict disease risk, a nomogram was constructed based on above m6A regulators. Cluster analysis divided the OA sample into different subgroups. Immune infiltration revealed the immune m6A regulators, which were validated using clinical samples. Eventually, a competing endogenous RNA (ceRNA) network was constructed.ResultsWe acquired five differentially expressed m6A regulators and a random forest model. The nomogram accurately predicted disease risk. We identified 122 differentially expressed genes between two m6A subgroups. The analysis of immune infiltration showed that YTHDF2 was an immune-related m6A regulator closely related with macrophages. In clinical samples, the protein and mRNA contents of YTHDF2 were consistent with the results of bioinformatic analysis. The ceRNA network based on YTHDF2 revealed 75 lncRNA nodes and 19 miRNA nodes.ConclusionYTHDF2 has a high diagnostic value in the synovitis of OA and significantly influences the immune status of patients. Hence, YTHDF2, a critical m6A regulator, may provide a biomarker for diagnosis and immune therapy of osteoarthritic synovitis.

Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue

Osteoarthritis is a chronic degenerative joint disease affecting millions of people worldwide, with no disease-modifying drugs currently available to treat the disease. Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a potential therapeutic target in osteoarthritis because of its ability to inhibit the catabolic metalloproteinases that drive joint damage by degrading the cartilage extracellular matrix. We previously found that suramin inhibits cartilage degradation through its ability to block endocytosis and intracellular degradation of TIMP-3 by low-density lipoprotein receptor-related protein 1 (LRP1), and analysis of commercially available suramin analogues indicated the importance of the 1,3,5-trisulfonic acid substitutions on the terminal naphthalene rings for this activity. Here we describe synthesis and structure–activity relationship analysis of additional suramin analogues using ex vivo models of TIMP-3 trafficking and cartilage degradation. This showed that 1,3,6-trisulfonic acid substitution of the terminal naphthalene rings was also effective, and that the protective activity of suramin analogues depended on the presence of a rigid phenyl-containing central region, with para/para substitution of these phenyl rings being most favourable. Truncated analogues lost protective activity. The physicochemical characteristics of suramin and its analogues indicate that approaches such as intra-articular injection would be required to develop them for therapeutic use.

TRPV4-mediated mitochondrial dysfunction induces pyroptosis and cartilage degradation in osteoarthritis via the Drp1-HK2 axis

Osteoarthritis (OA) is an age-related chronic degenerative disease with complex pathophysiological mechanisms. Accumulating evidence indicates that nod-like receptor pyrin domain 3 (NLRP3) inflammasome-mediated pyroptosis of chondrocytes plays a crucial role in the OA progression. Transient Receptor Potential Vanilloid 4 (TRPV4), described as a calcium-permeable cation channel, isassociated with proinflammatory factors and pyroptosis. In this study, we studied the potential functions of TRPV4 in chondrocyte pyroptosis and cartilage degradation. We found that lipopolysaccharides(LPS)-induced mitochondrial reactive oxygen species (mtROS) accumulation aggravated chondrocyte pyroptosis and cartilage degeneration. TRPV4 induces dynamin-related protein 1 (Drp1) mitochondrial translocation through the Ca2+-calmodulin-dependent protein kinase II (CaMKII) signaling pathway, which subsequently caused the mitochondrial dysfunction (e.g., mPTP over opening; Δψm depolarization; ATP production decreased; mtROS accumulation), pyroptosis and extracellular matrix (ECM) degradation through hexokinase 2 (HK2) dissociation from mitochondrial membrane. Moreover, TRPV4 inhibition reversed Drp1-involved chondrocyte pyroptosis and cartilage degeneration in the anterior cruciate ligament transection (ACLT) mouse model. Our findings revealed the internal mechanisms underlying TRPV4 regulation in chondrocytes and its intrinsic therapeutic efficacy for OA.

Astaxanthin as a Potent Antioxidant for Promoting Bone Health: An Up-to-Date Review.

In recent years, bone loss and its associated diseases have become a significant public health concern due to increased disability, morbidity, and mortality. Oxidative stress and bone loss are correlated, where oxidative stress suppresses osteoblast activity, resulting in compromised homeostasis between bone formation and resorption. This event causes upregulation of bone remodeling turnover rate with an increased risk of fractures and bone loss. Therefore, supplementation of antioxidants can be proposed to reduce oxidative stress, facilitate the bone remodeling process, suppress the initiation of bone diseases, and improve bone health. Astaxanthin (3,3'-dihydroxy-4-4'-diketo-β-β carotene), a potent antioxidant belonging to the xanthophylls family, is a potential ROS scavenger and could be a promising therapeutic nutraceutical possessing various pharmacological properties. In bone, astaxanthin enhances osteoblast differentiation, osteocytes numbers, and/or differentiation, inhibits osteoclast differentiation, cartilage degradation markers, and increases bone mineral density, expression of osteogenic markers, while reducing bone loss. In this review, we presented the up-to-date findings of the potential anabolic effects of astaxanthin on bone health in vitro, animal, and human studies by providing comprehensive evidence for its future clinical application, especially in treating bone diseases.

Pyruvate Dehydrogenase Kinase 1 inhibition mediated oxidative phosphorylation enhancement in cartilage promotes osteoarthritis progression

Osteoarthritis (OA) is a common disease characterized by cartilage degradation. Growing evidence showed that glucose metabolism impacts joint homeostasis and an imbalance between glycolysis and oxidative phosphorylation (OXPHOS) may exacerbate OA progression, however, a definitive link is yet to be established. Here, we report that pyruvate metabolism and oxidative phosphorylation pathway is enriched in OA cartilage through gene set enrichment analysis (GSEA) and expression of Pyruvate Dehydrogenase Kinase 1 (PDK1), an enzyme that can phosphorylate Pyruvate Dehydrogenase (PDH), and inhibit pyruvate fluxes into the tricarboxylic acid (TCA) cycle and to OXPHOS, in articular cartilage is notably reduced through destabilization of medial meniscus (DMM). Moreover, by inhibiting PDK1, cartilage loss is markedly accelerated in DMM-induced OA through extracellular matrix (ECM) degradation and apoptosis of chondrocytes. These results indicate that PDK1 is involved in the progression of OA through accelerating cartilage matrix degradation and synovium inflammation to ameliorate cartilage degeneration.

The Role of Genetics and Epigenetic Regulation in the Pathogenesis of Osteoarthritis.

Osteoarthritis (OA) is progressive disease characterised by cartilage degradation, subchondral bone remodelling and inflammation of the synovium. The disease is associated with obesity, mechanical load and age. However, multiple pro-inflammatory immune mediators regulate the expression of metalloproteinases, which take part in cartilage degradation. Furthermore, genetic factors also contribute to OA susceptibility. Recent studies have highlighted that epigenetic mechanisms may regulate the expression of OA-associated genes. This review aims to present the mechanisms of OA pathogenesis and summarise current evidence regarding the role of genetics and epigenetics in this process.