Osteoarthritis is not a disease, but rather an accumulation of predisposing factors. A systematic review

Introduction: Although they do not endanger the life of the individual, the major symptoms of osteoarthritis (OA), such as pain, inflammation and dysfunction, it will slowly decrease quality of life and performance, leading finally to disabilities. Due to the fact that this disease has no cure, strategies are still being sought to slow its evolution. The lack of understanding of the predisposing and triggering factors of OA, has led to different approaches to this pathology so discussed, but with modest results. This systematic review aims to debate the main phenomena underlying joint destruction in OA, and etiopathogenic theories. Materials and Methods: In this study were included 58 bibliographic sources, of which title 39 refers to OA, 6 with inflammation, 28 with cartilage, 3 with chondrocytes, and 5 with synovitis. In this study were discussed the etiopathogenic theories of OA which include: age, alteration of the cartilaginous matrix, alteration of chondrocyte metabolism, microtrauma and major trauma, inflammation of the joints - synovitis and obesity. Results: Increasing the level of understanding of predisposing factors, the occurrence of acute inflammatory phenomenon and the perpetuation of mechanisms that latently maintain chronic inflammation that over time develops a destructive effect on articular cartilage, would limit the negative effects of OA, delay the evolution and optimally combat that maintain the vicious circle: inflammation → production of enzymes → chondrolysis → inflammation. Conclusions: These studies contribute significantly to the understanding of destructive phenomena in OA. More studies are needed on the risk factors of OA and its production mechanisms, to find increasingly effective therapies that limiting its progression. Keywords: Osteoarthritis, etiopathogenic theories, chronic inflammation, age, obesity, cartilaginous matrixm, chondrocyte metabolism

Sirt5 Deficiency Causes Posttranslational Protein Malonylation and Dysregulated Cellular Metabolism in Chondrocytes Under Obesity Conditions

Objective Obesity accelerates the development of osteoarthritis (OA) during aging and is associated with altered chondrocyte cellular metabolism. Protein lysine malonylation (MaK) is a posttranslational modification (PTM) that has been shown to play an important role during aging and obesity. The objective of this study was to investigate the role of sirtuin 5 (Sirt5) in regulating MaK and cellular metabolism in chondrocytes under obesity-related conditions. Methods MaK and SIRT5 were immunostained in knee articular cartilage of obese db/db mice and different aged C57BL6 mice with or without destabilization of the medial meniscus surgery to induce OA. Primary chondrocytes were isolated from 7-day-old WT and Sirt5−/− mice and treated with varying concentrations of glucose and insulin to mimic obesity. Sirt5-dependent effects on MaK and metabolism were evaluated by western blot, Seahorse Respirometry, and gas/chromatography-mass/spectrometry (GC-MS) metabolic profiling. Results MaK was significantly increased in cartilage of db/db mice and in chondrocytes treated with high concentrations of glucose and insulin (GluhiInshi). Sirt5 was increased in an age-dependent manner following joint injury, and Sirt5 deficient primary chondrocytes had increased MaK, decreased glycolysis rate, and reduced basal mitochondrial respiration. GC-MS identified 41 metabolites. Sirt5 deficiency altered 13 distinct metabolites under basal conditions and 18 metabolites under GluhiInshi treatment. Pathway analysis identified a wide range of Sirt5-dependent altered metabolic pathways that include amino acid metabolism, TCA cycle, and glycolysis. Conclusion This study provides the first evidence that Sirt5 broadly regulates chondrocyte metabolism. We observed changes in SIRT5 and MaK levels in cartilage with obesity and joint injury, suggesting that the Sirt5-MaK pathway may contribute to altered chondrocyte metabolism that occurs during OA development.

Effect of Rubus idaeus Extracts in Murine Chondrocytes and Explants

Osteoarthritis is characterized by cartilage loss resulting from the activation of chondrocytes associated with a synovial inflammation. Activated chondrocytes promote an increased secretion of matrix proteases and proinflammatory cytokines leading to cartilage breakdown. Since natural products possess anti-inflammatory properties, we investigated the direct effect of Rubus idaeus extracts (RIE) in chondrocyte metabolism and cartilage loss. The effect of RIE in chondrocyte metabolism was analyzed in murine primary chondrocytes and cartilage explants. We also assessed the contribution of RIE in an inflammation environment by culturing mice primary chondrocytes with the supernatant of Raw 264.7 macrophage-like cells primed with RIE. In primary chondrocytes, RIE diminished chondrocyte hypertrophy (Col10), while increasing the expression of catabolic genes (Mmp-3, Mmp-13) and reducing anabolic genes (Col2a1, Acan). In cartilage explants, Rubus idaeus prevented the loss of proteoglycan (14.84 ± 3.07% loss of proteoglycans with IL1 alone vs. 3.03 ± 1.86% with IL1 and 100 µg/mL of RIE), as well as the NITEGE neoepitope expression. RIE alone reduced the expression of Il1 and Il6 in macrophages, without changes in Tnf and Cox2 expression. The secretome of macrophages pre-treated with RIE and transferred to chondrocytes decreases the gene and protein expression of Mmp-3 and Cox2. In conclusion, these data suggest that RIE may protect from chondrocyte catabolism and cartilage loss in inflammatory conditions. Further evaluations are need before considering RIE as a candidate for the treatment for osteoarthritis.

Sequential Epiphyseal Cartilage Changes of Femoral Heads in C57BL/6 Female Mice Treated with Excessive Glucocorticoids

Objective Excessive use of glucocorticoids (GCs) may cause adverse effects on the skeletal system in children. However, only a few studies have reported the effects of GCs on the epiphyseal cartilage. This study aimed to uncover the subsequent epiphyseal cartilage changes of immature femoral heads after excessive GC treatment in a mouse model and explain the pathological changes preliminarily. Design Female C57BL/6 mice were divided into control and model (excessive GC treatment) groups. The structure of the femoral heads was evaluated by using micro-computed tomography, hematoxylin-eosin staining, and safranin staining analyses. Immunohistochemistry was used to detect angiogenesis and cartilage metabolism. Western blotting and TUNEL staining were used to examine epiphyseal cartilage chondrocyte apoptosis. Primary chondrocytes were isolated from the femoral heads of healthy mice for in vitro studies. The effects of GCs on chondrocyte apoptosis and metabolism were determined by flow cytometry and Western blotting. Results The epiphyseal cartilage ossification had started at 4 weeks posttreatment in a portion of mice; the ossification presented as a sequential process in the model group, while the epiphyseal cartilage maintained an unossified state in the control group. Vascular invasion into the epiphyseal cartilage of the model mice was observed at 4 weeks posttreatment. GCs induced chondrocyte apoptosis and altered chondrocyte metabolism in the epiphyseal cartilage. Conclusions The epiphyseal cartilage ossification accelerated in the femoral heads of female C57BL/6 mice after excessive GC treatment. Increased chondrocyte apoptosis, altered chondrocyte metabolism, as well as increased vascular invasion, are the potential factors influencing epiphyseal cartilage ossification.

Sirt5 deficiency causes post-translational protein malonylation and dysregulated cellular metabolism in chondrocytes under obesity conditions

ABSTRACTObjectiveObesity accelerates the development of osteoarthritis (OA) during aging and is associated with altered chondrocyte cellular metabolism. The objective of this study was to investigate the role of sirtuin 5 (SIRT5) in regulating chondrocyte protein lysine malonylation (MaK) and cellular metabolism under obesity-related conditions.MethodsMaK and SIRT5 were immunostained in knee articular cartilage of obese db/db mice and different aged C57BL6 mice with or without destabilization of the medial meniscus (DMM) surgery to induce OA. Primary chondrocytes were isolated from 7-day-old WT and Sirt5−/− mice and treated with varying concentrations of glucose and insulin to mimic obesity. Sirt5-dependent effects on MaK and metabolism were evaluated by Western blot, Seahorse Respirometry, and gas/chromatography-mass/spectrometry (GC-MS) metabolic profiling.ResultsMaK was significantly increased in cartilage of db/db mice and in chondrocytes treated with high concentrations of glucose and insulin (GluhiInshi). Sirt5 protein was increased in an age-dependent manner following joint injury, and Sirt5 deficient primary chondrocytes had increased MaK, decreased glycolysis rate, and reduced basal mitochondrial respiration. GC-MS identified 41 metabolites. Sirt5 deficiency altered 13 distinct metabolites under basal conditions and 18 metabolites under GluhiInshi treatment. Pathway analysis identified a wide range of Sirt5-dependent altered metabolic pathways that include amino acid metabolism, TCA cycle, and glycolysis.ConclusionThis study provides the first evidence that Sirt5 broadly regulates chondrocyte metabolism. We observed changes in Sirt5 and MaK levels in cartilage with obesity and joint injury, suggesting that the Sirt5-MaK pathway may contribute to altered chondrocyte metabolism that occurs during OA development.

Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.