10-hydroxy-2-decenoic acid prevents osteoarthritis by targeting aspartyl ß hydroxylase and inhibiting chondrocyte senescence in male mice preclinically.

Osteoarthritis is a degenerative joint disease with joint pain as the main symptom, caused by fibrosis and loss of articular cartilage. Due to the complexity and heterogeneity of osteoarthritis, there is a lack of effective individualized disease-modifying osteoarthritis drugs in clinical practice. Chondrocyte senescence is reported to participate in occurrence and progression of osteoarthritis. Here we show that small molecule 10-hydroxy-2-decenoic acid suppresses cartilage degeneration and relieves pain in the chondrocytes, cartilage explants from osteoarthritis patients, surgery-induced medial meniscus destabilization or naturally aged male mice. We further confirm that 10-hydroxy-2-decenoic acid exerts a protective effect by targeting the glycosylation site in the Asp_Arg_Hydrox domain of aspartyl ß-hydroxylase. Mechanistically, 10-hydroxy-2-decenoic acid alleviate cellular senescence through the ERK/p53/p21 and GSK3ß/p16 pathways in the chondrocytes. Our study uncovers that 10-hydroxy-2-decenoic acid modulate cartilage metabolism by targeting aspartyl ß-hydroxylase to inhibit chondrocyte senescence in osteoarthritis. 10-hydroxy-2-decenoic acid may be a promising therapeutic drug against osteoarthritis.

Comparative study on the association between types of physical activity, physical activity levels, and the incidence of osteoarthritis in adults: the NHANES 2007-2020.

It is known that physical activity is beneficial for the prevention of osteoarthritis (OA), but specific discussions on which types and levels of physical activity are more effective in reducing the incidence of OA are restricted. This study is aimed at exploring the correlation concerning the types of physical activity, levels of physical activity, and the incidence of OA by assessing the participation in five typical forms of physical activity (vigorous work activity, vigorous recreational activity, moderate work activity, moderate recreational activity, and walking or bicycling). Cross-sectional study was conducted. Self-reported data on specific types of physical activity were obtained from individuals in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020 with the use of the Physical Activity Questionnaire (PAQ). The incidence of OA was assessed through the "Health Conditions" questionnaire section of NHANES. Weighted logistic regression analysis was employed to study the correlation between physical activity types and levels, and the incidence of OA. Different kinds of physical activity and physical activity levels have varying impacts on the incidence of OA. Among the types of physical activity, vigorous recreational activity and moderate recreational activity are found to have a preventive effect on OA. In terms of physical activity levels, low physical activity levels of moderate work activity are associated with an increased risk of OA, while moderate physical activity levels are confirmed to have a protective effect against OA in the age groups of 20-44 and 45-64. However, gender-stratified analyses reveal that both low and moderate physical activity levels provide protection against OA in males, with moderate physical activity levels showing a more significant protective effect.

Bergenin protects against osteoarthritis by inhibiting STAT3, NF-κB and Jun pathways and suppressing osteoclastogenesis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by articular cartilage destruction and subchondral bone reconstruction in the early stages. Bergenin (Ber) is a cytoprotective polyphenol found in many medicinal plants. It has been proven to have anti-inflammatory, antioxidant, and other biological activities, which may reveal its potential role in the treatment of OA. This study aimed to determine the potential efficacy of Ber in treating OA and explore the possible underlying mechanism through network pharmacology and validation experiments. The potential co-targets and processes of Ber and OA were predicted by using network pharmacology, including a Venn diagram for intersection targets, a protein‒protein interaction (PPI) network to obtain key potential targets, and GO and KEGG pathway enrichment to reveal the probable mechanism of action of Ber on OA. Subsequently, validation experiments were carried out to investigate the effects and mechanisms of Ber in treating OA in vitro and vivo. Ber suppressed IL-1ß-induced chondrocyte apoptosis and extracellular matrix catabolism by inhibiting the STAT3, NF-κB and Jun signalling pathway in vitro. Furthermore, Ber suppressed the expression of osteoclast marker genes and RANKL-induced osteoclastogenesis. Ber alleviated the progression of OA in DMM-induced OA mice model. These results demonstrated the protective efficacy and potential mechanisms of Ber against OA, which suggested that Ber could be adopted as a potential therapeutic agent for treating OA.

Dietary supplementation of vitamin B1 prevents the pathogenesis of osteoarthritis.

As the primary cause for chronic pain and disability in elderly individuals, osteoarthritis (OA) is one of the fastest-growing diseases due to the aging world population. To date, the impact of microenvironmental changes on the pathogenesis of OA remains poorly understood, greatly hindering the development of effective therapeutic approaches against OA. In this study, we profiled the differential metabolites in the synovial fluid from OA patients and identified the downregulation of vitamin B1 (VB1) as a metabolic feature in the OA microenvironment. In a murine destabilization of medial meniscus-induced OA model, supplementation of VB1 significantly mitigated the symptoms of OA. Cytokine array analysis revealed that VB1 treatment remarkably reduced the production of a pro-OA factor-C-C Motif Chemokine Ligand 2 (CCL2), in macrophages. Further evidence demonstrated that exogenous CCL2 counteracted the anti-OA function of VB1. Hence, our study unveils a unique biological function of VB1 and provides promising clues for the diet-based treatment of OA.

Updates in the skeletal and joint protective effects of tocotrienol: a mini review.

Osteoporosis and osteoarthritis continue to pose significant challenges to the aging population, with limited preventive options and pharmacological treatments often accompanied by side effects. Amidst ongoing efforts to discover new therapeutic agents, tocotrienols (TTs) have emerged as potential candidates. Derived from annatto bean and palm oil, TTs have demonstrated efficacy in improving skeletal and joint health in numerous animal models of bone loss and osteoarthritis. Mechanistic studies suggest that TTs exert their effects through antioxidant, anti-inflammatory, Wnt-suppressive, and mevalonate-modulating mechanisms in bone, as well as through self-repair mechanisms in chondrocytes. However, human clinical trials in this field remain scarce. In conclusion, TTs hold promise as agents for preventing osteoporosis and osteoarthritis, pending further evidence from human clinical trials.

Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle.

OBJECTIVE: Muscle wasting frequently occurs following joint trauma. Previous research has demonstrated that joint distraction in combination with treadmill exercise (TRE) can mitigate intra-articular inflammation and cartilage damage, consequently delaying the advancement of post-traumatic osteoarthritis (PTOA). However, the precise mechanism underlying this phenomenon remains unclear. Hence, the purpose of this study was to examine whether the mechanism by which TRE following joint distraction delays the progression of PTOA involves the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as its impact on muscle wasting. METHODS: Quadriceps samples were collected from patients with osteoarthritis (OA) and normal patients with distal femoral fractures, and the expression of PGC-1α was measured. The hinged external fixator was implanted in the rabbit PTOA model. One week after surgery, a PGC-1α agonist or inhibitor was administered for 4 weeks prior to TRE. Western blot analysis was performed to detect the expression of PGC-1α and Muscle atrophy gene 1 (Atrogin-1). We employed the enzyme-linked immunosorbent assay (ELISA) technique to examine pro-inflammatory factors. Additionally, we utilized quantitative real-time polymerase chain reaction (qRT-PCR) to analyze genes associated with cartilage regeneration. Synovial inflammation and cartilage damage were evaluated through hematoxylin-eosin staining. Furthermore, we employed Masson's trichrome staining and Alcian blue staining to analyze cartilage damage. RESULTS: The decreased expression of PGC-1α in skeletal muscle in patients with OA is correlated with the severity of OA. In the rabbit PTOA model, TRE following joint distraction inhibited the expressions of muscle wasting genes, including Atrogin-1 and muscle ring finger 1 (MuRF1), as well as inflammatory factors such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in skeletal muscle, potentially through the activation of PGC-1α. Concurrently, the production of IL-1ß, IL-6, TNF-α, nitric oxide (NO), and malondialdehyde (MDA) in the synovial fluid was down-regulated, while the expression of type II collagen (Col2a1), Aggrecan (AGN), SRY-box 9 (SOX9) in the cartilage, and superoxide dismutase (SOD) in the synovial fluid was up-regulated. Additionally, histological staining results demonstrated that TRE after joint distraction reduced cartilage degeneration, leading to a significant decrease in OARSI scores.TRE following joint distraction could activate PGC-1α, inhibit Atrogin-1 expression in skeletal muscle, and reduce C-telopeptides of type II collagen (CTX-II) in the blood compared to joint distraction alone. CONCLUSION: Following joint distraction, TRE might promote the activation of PGC-1α in skeletal muscle during PTOA progression to exert anti-inflammatory effects in skeletal muscle and joint cavity, thereby inhibiting muscle wasting and promoting cartilage regeneration, making it a potential therapeutic intervention for treating PTOA.

Molecular biomarker approaches to prevention of post-traumatic osteoarthritis.

Up to 50% of individuals develop post-traumatic osteoarthritis (PTOA) within 10 years following knee-joint injuries such as anterior cruciate ligament rupture or acute meniscal tear. Lower-extremity PTOA prevalence is estimated to account for ≥12% of all symptomatic osteoarthritis (OA), or approximately 5.6 million cases in the USA. With knowledge of the inciting event, it might be possible to 'catch PTOA in the act' with sensitive imaging and soluble biomarkers and thereby prevent OA sequelae by early intervention. Existing biomarker data in the joint-injury literature can provide insights into the pathogenesis and early risk trajectory related to PTOA and can help to elucidate a research agenda for preventing or slowing the onset of PTOA. Non-traumatic OA and PTOA have many clinical, radiological and genetic similarities, and efforts to understand early risk trajectories in PTOA might therefore contribute to the identification and classification of early non-traumatic OA, which is the most prevalent form of OA.

Potential Benefits of Statin Therapy in Reducing Osteoarthritis Risk: A Mendelian Randomization Study.

OBJECTIVE: The purpose of this study was to determine the causal effect of statins on osteoarthritis (OA) risk using Mendelian randomization (MR). METHODS: Single nucleotide polymorphism-based genome-wide association analyses of statins were collected from the UK Biobank and FinnGen dataset, and OA data were collected from the UK Biobank and Arthritis Research UK Osteoarthritis Genetics (arcOGEN) study. Two-sample MR analyses were performed using the inverse-variance weighted (IVW) technique. MR-Egger, weighted median, and weighted mode served as supplementary analyses. MR-Egger regression, Cochran's Q test, and Mendelian Randomization Pleiotropy Residual Sum and Outlier analysis were performed as sensitivity analyses. Hydroxymethylglutaryl-coenzyme A reductase (HMGCR) expression and OA risk were evaluated using summary data-based MR (SMR). RESULTS: MR analyses consistently supported a causal connection between statin use and OA risk. A causal effect was observed for atorvastatin (IVW: ß = -2.989, P = 0.003) and rosuvastatin (IVW: ß = -14.141, P = 0.006) treatment on hip OA. Meta-analysis showed the association between atorvastatin and knee OA was statistically significant (odds ratio 0.15; P = 0.004). Simvastatin use exhibited a protective effect against knee (IVW: ß = -1.056, P = 0.004) and hip OA (IVW: ß = -1.405, P = 0.001). Statin medication showed a protective effect on hip OA (IVW: ß = -0.054, P = 0.013). HMGCR correlated significantly with a reduced risk of knee OA (ß = -0.193, PSMR = 0.017), rather than hip OA (ß = 0.067, PSMR = 0.502), which suggested that statins' protective effect on OA may not be related to its lipid-lowering effect. CONCLUSION: This MR study provides compelling evidence that statin treatment may be a protective factor for OA. Further research is required to clarify its underlying mechanism.

Circular RNA Gtdc1 Protects Against Offspring Osteoarthritis Induced by Prenatal Prednisone Exposure by Regulating SRSF1-Fn1 Signaling.

Chondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0-20 and underwent long-distance running during postnatal weeks (PWs) 24-28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long-distance running, the PPE group exhibited more typical osteoarthritis-like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48-linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFß pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra-articular injection of offspring with AAV-circGtdc1 ameliorated PPE-induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1-Srsf1-Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE-induced chondrodysplasia.

Inhibition of complement C3 prevents osteoarthritis progression in guinea pigs by blocking STAT1 activation.

Osteoarthritis (OA) is one of the leading causes of disability, affecting over 500 million adults worldwide. Previous studies have found that various inflammatory factors can contribute to the pathogenesis of OA, including complement factors in the synovial fluid of OA patients. However, the pathogenesis of this disease is still not known, and the only therapy of severe OA is total joint replacements. Total joint replacements are invasive, expensive, and affect quality of life. Here we show that when human articular chondrocytes are stimulated with pro-inflammatory mediator interleukin-1ß (IL-1ß) there is an increase in inflammatory factors including complement component 3 (C3). We also found the transcription factor, signal transducer and activator of transcription 1 (STAT1), is responsible for increased C3 expression after IL-1ß stimulation in human articular chondrocytes. A specific STAT1 inhibitor, fludarabine, attenuates the hyper-expression of C3 and delays/prevents spontaneous OA in Dunkin-Hartley guinea pigs. Since fludarabine is already clinically used for chemotherapy, this study has great translational potential as a unique disease-modifying osteoarthritis drug (DMOAD) in treating primary OA.

Investigation Into the Effects of Intra-Articular Steroid on Post-Traumatic Osteoarthritis in Distal Radius Fractures: A Randomized Controlled Pilot Study.

PURPOSE: The aim of this prospective, randomized, controlled, double-blinded pilot study was to determine the rates of post-traumatic osteoarthritis and assess joint space width in the presence or absence of a single intra-articular injection of corticosteroid after an acute, intra-articular distal radius fracture (DRF). METHODS: Forty patients received a single, intra-articular, radiocarpal joint injection of 4 mg of dexamethasone (DEX) (n = 19) or normal saline placebo (n = 21) within 2 weeks of a surgically or nonsurgically treated intra-articular DRF. The primary outcome measure was minimum radiocarpal joint space width (mJSW) on noncontrast computed tomography scans at 2 years postinjection. Secondary outcomes were obtained at 3 months, 6 months, 1 year, and 2 years postinjection and included Disabilities of the Arm, Shoulder, and Hand; Michigan Hand Questionnaire; Patient-Rated Wrist Evaluation; wrist range of motion; and grip strength. RESULTS: At 2-year follow-up, there was no difference in mean mJSW between the DEX group (2.2 mm; standard deviation, 0.6; range, 1.4-3.2) and the placebo group (2.3 mm; standard deviation, 0.7; range, 0.9-3.9). Further, there were no differences in any secondary outcome measures at any postinjection follow-up interval. CONCLUSIONS: Radiocarpal joint injection of corticosteroid within 2 weeks of an intra-articular DRF does not appear to affect the development of post-traumatic osteoarthritis within 2 years follow-up in a small pilot cohort. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Effects of emulsified and non-emulsified palm tocotrienol on bone and joint health in ovariectomised rats with monosodium iodoacetate-induced osteoarthritis.

Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.

Treatment with PB125® Increases Femoral Long Bone Strength in 15-Month-Old Female Hartley Guinea Pigs.

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a transcription factor that serves as a master regulator of anti-inflammatory agents, phase I xenobiotic, and phase II antioxidant enzymes, all of which provide a cytoprotective role during disease progression. We hypothesized that oral administration of a purported phytochemical Nrf2-activator, PB125®, would increase long bone strength in aging Hartley guinea pigs, a model prone to musculoskeletal decline. Male (N = 56) and female (N = 56) guinea pigs were randomly assigned to receive daily oral treatment with either PB125® or vehicle control. Animals were treated for a consecutive 3-months (starting at 2-months of age) or 10-months (starting at 5-months of age) and sacrificed at 5-months or 15-months of age, respectively. Outcome measures included: (1) ANY-maze™ enclosure monitoring, (2) quantitative microcomputed tomography, and (3) biomechanical testing. Treatment with PB125® for 10 months resulted in increased long bone strength as determined by ultimate bending stress in female Hartley guinea pigs. In control groups, increasing age resulted in significant effects on geometric and structural properties of long bones, as well as a trending increase in ultimate bending stress. Furthermore, both age and sex had a significant effect on the geometric properties of both cortical and trabecular bone. Collectively, this work suggests that this nutraceutical may serve as a promising target and preventive measure in managing the decline in bone mass and quality documented in aging patients. Auxiliary to this main goal, this work also capitalized upon 5 and 15-month-old male and female animals in the control group to characterize age- and sex-specific differences on long bone geometric, structural, and material properties in this animal model.

Low-Molecular-Weight Fish Collagen Peptide (Valine-Glycine-Proline-Hydroxyproline-Glycine-Proline-Alanine-Glycine) Prevents Osteoarthritis Symptoms in Chondrocytes and Monoiodoacetate-Injected Rats.

The objective of this study was to investigate the effect of low-molecular-weight fish collagen (valine-glycine-proline-hydroxyproline-glycine-proline-alanine-glycine; LMWCP) on H2O2- or LPS-treated primary chondrocytes and monoiodoacetate (MIA)-induced osteoarthritis rat models. Our findings indicated that LMWCP treatment exhibited protective effects by preventing chondrocyte death and reducing matrix degradation in both H2O2-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. This was achieved by increasing the levels of aggrecan, collagen type I, collagen type II, TIMP-1, and TIMP-3, while simultaneously decreasing catabolic factors such as phosphorylation of Smad, MMP-3, and MMP-13. Additionally, LMWCP treatment effectively suppressed the activation of inflammation and apoptosis pathways in both LPS-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. These results suggest that LMWCP supplementation ameliorates the progression of osteoarthritis through its direct impact on inflammation and apoptosis in chondrocytes.

PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy.

INTRODUCTION: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1ß (IL -1ß). METHODS: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo. RESULTS: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1ß-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545. CONCLUSION: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.

Kukoamine A protects mice against osteoarthritis by inhibiting chondrocyte inflammation and ferroptosis via SIRT1/GPX4 signaling pathway.

AIMS: Osteoarthritis (OA) is one of the common chronic degenerative joint diseases, characterized by cartilage damage, subchondral bone changes, osteophyte formation, and synovitis. Kukoamine A (KuKA) is a bioactive compound isolated from Lycium chinense which is known as its anti-inflammatory activity. In this study, we detected the regulatory role of KuKA on OA both in vivo and in vitro. MATERIALS AND METHODS: Mouse chondrocytes were cultured and mouse model of OA was established. Inflammatory mediator was measured by ELISA. The signaling pathway was tested by western blot analysis. KEY FINDINGS: KuKA inhibited IL-1ß-induced PGE2 and NO production and iNOS and COX-2 expression. IL-1ß-induced MMP1 and MMP3 production was attenuated by KuKA. IL-1ß-induced MDA, iron, and ROS were alleviated by KuKA. Meanwhile, GSH content, GPX4, Ferritin, SIRT1, Nrf2, and HO-1 expression were upregulated by KuKA. Furthermore, the inhibitory role of KuKA on IL-1ß-induced inflammation, MMPs production, and ferroptosis were reversed by SIRT1 inhibitor. In vivo, KuKA could attenuate OA development in mouse model. KuKA markedly alleviated MMP1, MMP3, iNOS, and COX2 expression in OA mice. SIGNIFICANCE: In conclusion, KuKA could inhibit OA development through suppressing chondrocyte inflammation and ferroptosis via SIRT1/GPX4 signaling pathway.

Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration. Autophagy is associated with chondrocyte homeostasis and exhibits a role in protecting against OA pathogenesis. Geniposide (GEN), an iridoid glycoside extracted from Eucommia ulmoides Oliv, acts as an activator of GLP-1R, which can stimulate autophagy. The AMPK/mTOR signaling pathway participates in the mediation of autophagy, and GLP-1R may act as an upstream factor of AMPK. However, whether GEN mediates the autophagic responses by activating the GLP-1R/AMPK/mTOR signaling pathway in OA chondrocytes is still unclear. In the current study, attenuated autophagy in MIA-induced rat OA models was observed, as shown by up-regulated expression of p62 and down-regulated expression of Beclin-1 and LC3-II/I. GEN stimulated autophagy and protected OA cartilage by up-regulating GLP-1R expression. In addition, GEN could enhance AMPK phosphorylation and down-regulate mTOR expression in IL-1ß-treated C28/I2 cells. Inhibition of AMPK or activation of mTOR could reverse the stimulatory effects of GEN on autophagy. Furthermore, a GLP-1R inhibitor Exendin 9-39 could eliminate the chondroprotective effects of GEN by suppressing the AMPK/mTOR signaling pathway. Conclusively, Geniposide exhibits protective effects against osteoarthritis development by stimulating autophagy via activating the GLP-1R/AMPK/mTOR signaling pathway.

[Peptides prevent the forming of secretory phenotype of chondrocytes associated with the aging.]

Secretory phenotype associated with the aging (SASP) of chondrocytes forms the conditions for the musculoskeletal system diseases development, in particular, osteoarthritis (OA). The search for effective methods for OA treating is an urgent task of molecular gerontology. The purpose of this work is to characterize the SASP of chondrocytes and to conduct a comparative assessment of the effect of AED peptide and the cartilage polypeptide complex (CPC). It was found that chondrocyte's SASP is characterized by an increase of the synthesis of p16, p21, p53 pro-apoptotic proteins, TNF-α, IL-1α pro-inflammatory cytokines and a decrease of Sirt1synthesis. Peptides AED and CPC normalize the synthesis of molecules that form SASP of chondrocytes. This effect may explain their geroprotective effect and effectiveness in studies of various pathologies of the musculoskeletal system, including OA.

Targeting the Inflammatory Hallmarks of Obesity-Associated Osteoarthritis: Towards Nutraceutical-Oriented Preventive and Complementary Therapeutic Strategies Based on n-3 Polyunsaturated Fatty Acids.

Obesity (Ob), which has dramatically increased in the last decade, is one of the main risk factors that contribute to the incidence and progression of osteoarthritis (OA). Targeting the characteristics of obesity-associated osteoarthritis (ObOA) may offer new chances for precision medicine strategies in this patient cohort. First, this review outlines how the medical perspective of ObOA has shifted from a focus on biomechanics to the significant contribution of inflammation, mainly mediated by changes in the adipose tissue metabolism through the release of adipokines and the modification of fatty acid (FA) compositions in joint tissues. Preclinical and clinical studies on n-3 polyunsaturated FAs (PUFAs) are critically reviewed to outline the strengths and weaknesses of n-3 PUFAs' role in alleviating inflammatory, catabolic and painful processes. Emphasis is placed on potential preventive and therapeutic nutritional strategies based on n-3 PUFAs, with a focus on ObOA patients who could specifically benefit from reformulating the dietary composition of FAs towards a protective phenotype. Finally, tissue engineering approaches that involve the delivery of n-3 PUFAs directly into the joint are explored to address the perspectives and current limitations, such as safety and stability issues, for implementing preventive and therapeutic strategies based on dietary compounds in ObOA patients.

Astaxanthin prevents osteoarthritis by blocking Rspo2-mediated Wnt/ß-catenin signaling in chondrocytes and abolishing Rspo2-related inflammatory factors in macrophages.

Chondrocyte degeneration and classically activated macrophage (AM)-related inflammation play critical roles in osteoarthritis (OA). Here, we explored the effects of astaxanthin and Rspo2 on OA in vitro and in vivo. We observed that the Rspo2 gene was markedly elevated in synovial tissues of OA patients compared with healthy controls. In 2D cultures, Rspo2 and inflammatory factors were enhanced in AMs compared with nonactivated macrophages (NMs), and the protein expression levels of Rspo2, ß-catenin, and inflammatory factors were increased, and anabolic markers were reduced in osteoarthritic chondrocytes (OACs) compared to normal chondrocytes (NCs). Astaxanthin reversed these changes in AMs and OACs. Furthermore, Rspo2 shRNA significantly abolished inflammatory factors and elevated anabolic markers in OACs. In NCs cocultured with AM, and in OACs cocultured with AMs or NMs, astaxanthin reversed these changes in these coculture systems and promoted secretion of Rspo2, ß-catenin and inflammatory factors and suppressed anabolic markers compared to NCs or OACs cultured alone. In AMs, coculture with NCs resulted in a slight elevation of Rspo2 and AM-related genes, but not protein expression, compared to culture alone, but when cocultured with OACs, these inflammatory mediators were significantly enhanced at both the gene and protein levels. Astaxanthin reversed these changes in all the groups. In vivo, we observed a deterioration in cartilage quality after intra-articular injection of Rspo2 associated with medial meniscus (DMM)-induced instability in the OA group, and astaxanthin was protective in these groups. Our results collectively revealed that astaxanthin attenuated the process of OA by abolishing Rspo2 both in vitro and in vivo.