Osteomodulin downregulation is associated with osteoarthritis development.

Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

Synthesis by solid route and physicochemical characterizations of blends of calcium orthophosphate powders and mesoporous silicon particles.

The purpose of the study was to investigate the synthesis of economic calcium phosphate powders from recycled oyster shells, using a ball milling method. The oyster shell powder and a calcium pyrophosphate powder were used as starting materials and ball milled, then heat treated at 1,050°C for 5 h to produce calcium phosphate powders through a solid-state reaction. Electrochemically synthesized mesoporous silicon microparticles were then added to the prepared phosphate powders by mechanical mixer. The final powders were characterized using X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy to analyze their chemical composition and determine the most suitable process conditions. The biocompatibility of the produced powders was also tested in vitro using murine cells and the results showed good biocompatibility.

Interleukins, growth factors, and transcription factors are key targets for gene therapy in osteoarthritis: A scoping review.

Objective: Osteoarthritis (OA) is the most common degenerative joint disease, characterized by a progressive loss of cartilage associated with synovitis and subchondral bone remodeling. There is however no treatment to cure or delay the progression of OA. The objective of this manuscript was to provide a scoping review of the preclinical and clinical studies reporting the effect of gene therapies for OA. Method: This review followed the JBI methodology and was reported in accordance with the PRISMA-ScR checklist. All research studies that explore in vitro, in vivo, or ex vivo gene therapies that follow a viral or non-viral gene therapy approach were considered. Only studies published in English were included in this review. There were no limitations to their date of publication, country of origin, or setting. Relevant publications were searched in Medline ALL (Ovid), Embase (Elsevier), and Scopus (Elsevier) in March 2023. Study selection and data charting were performed by two independent reviewers. Results: We found a total of 29 different targets for OA gene therapy, including studies examining interleukins, growth factors and receptors, transcription factors and other key targets. Most articles were on preclinical in vitro studies (32 articles) or in vivo animal models (39 articles), while four articles were on clinical trials related to the development of TissueGene-C (TG-C). Conclusion: In the absence of any DMOAD, gene therapy could be a highly promising treatment for OA, even though further development is required to bring more targets to the clinical stage.

Curcuma longa and Boswellia serrata Extracts Modulate Different and Complementary Pathways on Human Chondrocytes In Vitro: Deciphering of a Transcriptomic Study.

Objectives: Curcuma longa (CL) and Boswellia serrata (BS) extracts are used to relieve osteoarthritis symptoms. The aim of this in vitro study was to investigate their mechanisms of action at therapeutic plasmatic concentrations on primary human osteoarthritic (OA) chondrocytes. Methods: BS (10-50 µg/ml) and CL (0.4-2 µg/ml corresponding to 1-5 µM of curcumin) were evaluated separately or in combination on primary chondrocytes isolated from 17 OA patients and cultured in alginate beads. Ten patients were used for RNA-sequencing analysis. Proteomic confirmation was performed either by immunoassays in the culture supernatant or by flow cytometry for cell surface markers after 72 h of treatment. Results: Significant gene expression modifications were already observed after 6 h of treatment at the highest dose of CL (2 µg/ml) while BS was significantly effective only after 24 h of treatment irrespective of the concentration tested. The most over-expressed genes by CL were anti-oxidative, detoxifying, and cytoprotective genes involved in the Nrf2 pathway. Down-regulated genes were principally pro-inflammatory cytokines and chemokines. Inversely, BS anti-oxidant/detoxifying activities were related to the activation of Nrf1 and PPARα pathways. BS anti-inflammatory effects were associated with the increase in GDF15, decrease in cholesterol cell intake and fatty acid metabolism-involved genes, and down-regulation of Toll-like receptors (TLRs) activation. Similar to CL, BS down-regulated ADAMTS1, 5, and MMP3, 13 genes expression. The combination of both CL and BS was significantly more effective than CL or BS alone on many genes such as IL-6, CCL2, ADAMTS1, and 5. Conclusion: BS and CL have anti-oxidative, anti-inflammatory, and anti-catabolic activities, suggesting a protective effect of these extracts on cartilage. Even if they share some mechanism of action, the two extracts act mainly on distinct pathways, and with different time courses, justifying their association to treat osteoarthritis.

P2-Na0.67Mn0.85Al0.15O2 and NaMn2O4 Blend as Cathode Materials for Sodium-Ion Batteries Using a Natural ß-MnO2 Precursor.

Sodium-ion batteries (NIBs) are promising candidates for specific stationary applications considering their low-cost and cost-effective energetic property compared to lithium-ion batteries (LIBs). Additional cost cutbacks are achievable by employing natural materials as active cathode materials for NIBs. In this work, we report the use of natural pyrolusite (ß-MnO2) as a precursor for the synthesis of a NaMnO blend (a mixture of layered P2-Na0.67Mn0.85Al0.15O2 without any doping technique combined with a post-spinel NaMn2O4 without any high-pressure synthesis). The synthesized powder was characterized by XRD, evidencing these two phases, along with two additional phases. Tests for Na-ion insertion registered a reversible discharge capacity of 104 mA h/g after 10 cycles with a well-defined plateau at 2.25 V. After 500 cycles at a C/4 current density, a high Coulombic efficiency between 96 and 99% was achieved, with an overall 25% capacity retention loss. These pilot tests are encouraging; they provide economic relief since the natural material is abundant (low-cost). Desirable, energetic assurances and ecological confirmations are obtainable if these materials are implemented in large-scale stationary applications. The synthesis technique does not use any toxic metals or toxic solvents and has limited side product formation.

Syndecan-4 Is Increased in Osteoarthritic Knee, but Not Hip or Shoulder, Articular Hypertrophic Chondrocytes.

OBJECTIVE: Syndecan-4 plays a critical role in cartilage degradation during osteoarthritis (OA). The aim of this study was to investigate the expression and localization of syndecan-4 in different OA joint tissues. DESIGN: Syndecan-4 mRNA levels were quantified by reverse transcription-polymerase chain reaction in human OA primary cells. Syndecan-4 was localized by immunohistochemistry in knee, hip, or shoulder OA bone/cartilage biopsies. Syndecan-4 was quantified by immunoassay in chondrocytes culture supernatant and cell fraction. RESULTS: Using immunochemistry, syndecan-4 was observed in chondrocytes clusters in the superficial zone of OA knee, but not in OA hip or shoulder cartilage. No significant difference was detected in syndecan-4 expression level in sclerotic compared with nonsclerotic osteoblasts or in inflamed synoviocytes compared to normal/reactive ones. Differentiated hypertrophic chondrocytes from knee, but not from hip cartilage, expressed more syndecan-4 than nonhypertrophic cells. Using an immunoassay for the extracellular domain of syndecan-4, we found 68% of the syndecan-4 in the culture supernatant of OA chondrocytes culture, suggesting that a large majority of the syndecan-4 is shed and released in the extracellular medium. The shedding rate was not affected by hypertrophic differentiation state of the chondrocytes or their joint origin. CONCLUSIONS: Even if chondrocytes clusters are seen in OA knee, hip and shoulder cartilage and hypertrophic differentiation appears in knee and hip OA articular chondrocytes, syndecan-4 synthesis only increased in knee. These findings suggest the presence of biochemical difference between articular cartilage according to their location and that syndecan-4 could be a biochemical marker specific for knee OA.

Composition Analysis and Pharmacological Activity of Avocado/Soybean Unsaponifiable Products Used in the Treatment of Osteoarthritis.

Objective: Avocado/soybean unsaponifiables (ASUs) are commonly used to treat OA symptoms. However, there are many ASU mixtures on the market with differing compositions and pharmacological activities. This study aimed to compare the composition and pharmacological activity of seven commercially available ASU products on human osteoarthritis chondrocytes. Methods: The contents of the lipidic part of ASUs were characterized by gas chromatography analysis using a VARIAN 3400 chromatograph. The pharmacological activity of the ASU products was tested on human osteoarthritis chondrocytes cultured in alginate beads. Their effects were evaluated on aggrecan, interleukin (IL)-6 and -8, and matrix metalloproteases (MMP)-3 using immunoassays and on nitric oxide through measurement of nitrite via spectrometry. Results: PIASCLEDINE-ExpASU® showed a specific profile with the presence of chromatographic peaks corresponding to an alkyl furan fraction and alkyl triols. PIASCLEDINE-ExpASU®, Persemax, Insaponifiable 300, Arthrocen, and Arthocare contained quantifiable amounts of tocopherol, while tocopherol was undetectable in Avovida and Saponic. Squalene was found only in PIASCLEDINE-ExpASU®. The abundance of sterols varied depending on the product. PIASCLEDINE-ExpASU® was the most active of the tested ASU products in inhibiting nitric oxide, IL-6, and IL-8 production by chondrocytes. With the exception of Saponic and Persemax, all the ASU mixtures either slightly or significantly increased aggrecan production. MMP-3 levels were significantly decreased by Insaponifiable 300 and PIASCLEDINE-ExpASU® and significantly increased by Saponic. Conclusion: The composition of PIASCLEDINE-ExpASU® is different to that of the other evaluated ASU mixtures. This specific composition explains its better pharmacological activity, including the higher inhibitory effect on pro-inflammatory and pro-catabolic factors. Our findings are helpful in providing a basis for understanding the symptomatic effect of PIASCLEDINE-ExpASU® in patients with osteoarthritis.

Towards valorizing natural coals in sodium-ion batteries: impact of coal rank on energy storage.

Coal samples of different ranks were investigated through various compositional, morphological/structural, and textural experiments prior to their electrochemical implementation in Na-ion half-cells. The purity of coals proved insignificant while distinctions in the flake size, pore width, pore distribution, ID/IG ratio, crystallite parameters (La and Lc) along with adjacent parameters, such as the R-empirical parameter, i.e., limited parallel graphene stacking proved more relevant for Na+ storage into the negative host electrodes. Coal powders were identified via a two-step TGA analysis technique displaying the overall carbon content of the coals and the impurities. Coal-based anode materials were prepared from raw and pyrolyzed coals (at 800 °C under argon gas-flow) and cycled in Na-ion half-cells to further investigate the impact of the coal rank on the energetic properties. High volatile bituminous coal with lower graphene stacking and augmented nanoscopic pores delivered higher reversible capacity in comparison with semi-anthracite coal, whether in their raw (67 vs. 54 mAh/g) or pyrolyzed (214 vs. 64 mAh/g) states, respectively vs. Na/Na+. The dominance of HVBC over SAC due to enhanced properties as R-empirical parameter, ID/IG ratio, and internal porosity. This study provides an exhaustive methodology to assess other carbonaceous anode materials further to evaluate their energy storage capabilities.

From Translation to Protein Degradation as Mechanisms for Regulating Biological Functions: A Review on the SLRP Family in Skeletal Tissues.

The extracellular matrix can trigger cellular responses through its composition and structure. Major extracellular matrix components are the proteoglycans, which are composed of a core protein associated with glycosaminoglycans, among which the small leucine-rich proteoglycans (SLRPs) are the largest family. This review highlights how the codon usage pattern can be used to modulate cellular response and discusses the biological impact of post-translational events on SLRPs, including the substitution of glycosaminoglycan moieties, glycosylation, and degradation. These modifications are listed, and their impacts on the biological activities and structural properties of SLRPs are described. We narrowed the topic to skeletal tissues undergoing dynamic remodeling.

The secretome of skeletal muscle cells: A systematic review.

Background: Proteomic studies of the secretome of skeletal muscle cells can help us understand the processes that govern the synthesis, systemic interactions and organization of skeletal muscle and identify proteins that are involved in muscular adaptations to exercise, ageing and degeneration. In this systematic review, we aimed to summarize recent mass-spectrometry based proteomics discoveries on the secretome of skeletal muscle cells in response to disease, exercise or metabolic stress. Methods: A literature search was performed in the Medline/Ovid and Scopus electronic bibliographic databases. Only papers reporting the analysis of the secretome by mass spectrometry were included. Results: A total of 19 papers met the inclusion criteria for this systematic review. These papers included comparative analysis of differentially expressed proteins between healthy and unhealthy muscle cells and comparison of the secretome of skeletal muscle cells during myogenesis and after insulin stimulation or exercising. The proteins were separated into several categories and their differential secretion was compared. In total, 654 proteins were listed as being present in the secretome of muscle cells. Among them, 30 proteins were differentially regulated by physical exercise, 130 during myogenesis, 114 by dystrophin deficiency, 26 by muscle atrophy, 27 by insulin stimulation and finally 176 proteins secreted by insulin-resistant muscle cells. Conclusions: This systematic review of the secretome of skeletal muscle cell in health and disease provides a comprehensive overview of the most regulated proteins in pathological or physiological conditions. These proteins might be therapeutic targets or biochemical markers of muscle diseases.

The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature.

During the osteoarthritis (OA) process, activation of immune systems, whether innate or adaptive, is strongly associated with low-grade systemic inflammation. This process is initiated and driven in the synovial membrane, especially by synovium cells, themselves previously activated by damage-associated molecular patterns (DAMPs) released during cartilage degradation. These fragments exert their biological activities through pattern recognition receptors (PRRs) that, as a consequence, induce the activation of signaling pathways and beyond the release of inflammatory mediators, the latter contributing to the vicious cycle between cartilage and synovial membrane. The primary endpoint of this review is to provide the reader with an overview of these many molecules categorized as DAMPs and the contribution of the latter to the pathophysiology of OA. We will also discuss the different strategies to control their effects. We are convinced that a better understanding of DAMPs, their receptors, and associated pathological mechanisms represents a decisive issue for degenerative joint diseases such as OA.

Coll2-1 and Coll2-1NO2 as exemplars of collagen extracellular matrix turnover - biomarkers to facilitate the treatment of osteoarthritis?

Introduction: Osteoarthritis (OA) is the most common form of arthritis. However, there are no structure or disease-modifying OA drugs (DMOADs). Introducing personalized healthcare to patients and health-care practitioners is a high priority for the management of arthritic and musculoskeletal diseases. However, there are no biomarker tools that can be used for patient stratification, disease management, and drug development. Biomarkers are capable of diagnosing and prognosing some arthritic and musculoskeletal diseases. Cartilage-based biomarkers have the potential to be used in this context to guide the precision treatment of OA. Areas covered: The aim of this review is to focus on the pre-clinical and clinical utility of the Coll2-1 and Coll2-1NO2 biomarkers as unique cartilage-based biomarkers that can guide the development of new treatments for OA. This expert report will begin with a background to collagens and their important biomechanical roles in the musculoskeletal system, but particularly cartilage, before exploring the data and scientific evidence to support the utility of Coll2-1 and Coll2-1NO2 as unique biomarkers. Expert opinion: This review summarises the authors' expert view on the pre-clinical and clinical utility of the Coll2-1 and Coll2-1NO2 biomarkers and their potential for use as drug development tools.

Glycation marker glucosepane increases with the progression of osteoarthritis and correlates with morphological and functional changes of cartilage in vivo.

BACKGROUND: Changes of serum concentrations of glycated, oxidized, and nitrated amino acids and hydroxyproline and anticyclic citrullinated peptide antibody status combined by machine learning techniques in algorithms have recently been found to provide improved diagnosis and typing of early-stage arthritis of the knee, including osteoarthritis (OA), in patients. The association of glycated, oxidized, and nitrated amino acids released from the joint with development and progression of knee OA is unknown. We studied this in an OA animal model as well as interleukin-1ß-activated human chondrocytes in vitro and translated key findings to patients with OA. METHODS: Sixty male 3-week-old Dunkin-Hartley guinea pigs were studied. Separate groups of 12 animals were killed at age 4, 12, 20, 28 and 36 weeks, and histological severity of knee OA was evaluated, and cartilage rheological properties were assessed. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1ß. Human patients with early and advanced OA and healthy controls were recruited, blood samples were collected, and serum or plasma was prepared. Serum, plasma, and culture medium were analyzed for glycated, oxidized, and nitrated amino acids. RESULTS: Severity of OA increased progressively in guinea pigs with age. Glycated, oxidized, and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p < 0.0001) and instantaneous modulus (r = 0.52-0.56; p < 0.0001), oxidation free adducts correlated positively with OA severity (p < 0.0009-0.0062), and hydroxyproline correlated positively with cartilage thickness (p < 0.0003-0.003). Interleukin-1ß increased the release of glycated and nitrated amino acids from chondrocytes in vitro. In clinical translation, plasma glucosepane was increased 38% in early-stage OA (p < 0.05) and sixfold in patients with advanced OA (p < 0.001) compared with healthy controls. CONCLUSIONS: These studies further advance the prospective role of glycated, oxidized, and nitrated amino acids as serum biomarkers in diagnostic algorithms for early-stage detection of OA and other arthritic disease. Plasma glucosepane, reported here for the first time to our knowledge, may improve early-stage diagnosis and progression of clinical OA.

Comparison of secretome from osteoblasts derived from sclerotic versus non-sclerotic subchondral bone in OA: A pilot study.

OBJECTIVE: Osteoarthritis (OA) is characterized by cartilage degradation but also by other joint tissues modifications like subchondral bone sclerosis. In this study, we used a proteomic approach to compare secretome of osteoblast isolated from sclerotic (SC) or non sclerotic (NSC) area of OA subchondral bone. DESIGN: Secretome was analyzed using differential quantitative and relative label free analysis on nanoUPLC G2 HDMS system. mRNA of the more differentially secreted proteins were quantified by RT-PCR in cell culture from 5 other patients. Finally, osteomodulin and fibulin-3 sequences were quantified by western blot and immunoassays in serum and culture supernatants. RESULTS: 175 proteins were identified in NSC osteoblast secretome. Data are available via ProteomeXchange with identifier PXD008494. Compared to NSC osteoblast secretome, 12 proteins were significantly less secreted (Osteomodulin, IGFBP5, VCAM-1, IGF2, 78 kDa glucose-regulated protein, versican, calumenin, IGFBP2, thrombospondin-4, periostin, reticulocalbin 1 and osteonectin), and 13 proteins were significantly more secreted by SC osteoblasts (CHI3L1, fibulin-3, SERPINE2, IGFBP6, SH3BGRL3, SERPINE1, reticulocalbin3, alpha-2-HS-glycoprotein, TIMP-2, IGFBP3, TIMP-1, SERPINF1, CSF-1). Similar changes in osteomodulin, IGF2, SERPINE1, fibulin-3 and CHI3L1 mRNA levels were observed. ELISAs assays confirm the decrease by half of osteomodulin protein in SC osteoblasts supernatant compared to NSC and in OA patients serum compared to healthy subjects. Fibulin-3 epitopes Fib3-1, Fib3-2 and Fib3-3 were also increased in SC osteoblasts supernatant compared to NSC. CONCLUSIONS: We highlighted some proteins differentially secreted by the osteoblasts coming from OA subchondral bone sclerosis. These changes contribute to explain some features observed in OA subchondral bone, like the increase of bone remodeling or abnormalities in bone matrix mineralization. Among identified proteins, osteomodulin was found decreased and fibulin-3 increased in serum of OA patients. These findings suggest that osteomodulin and fibulin-3 fragments could be biomarkers to monitor early changes in subchondral bone metabolism in OA.

Review of Soluble Biomarkers of Osteoarthritis: Lessons From Animal Models.

Objective Osteoarthritis (OA) is one of the leading causes of disability within the adult population. Currently, its diagnosis is mainly based on clinical examination and standard radiography. To date, there is no way to detect the disease at a molecular level, before the appearance of structural changes and symptoms. So an attractive alternative for monitoring OA is the measurement of biochemical markers in blood, urine, or synovial fluid, which could reflect metabolic changes in joint tissue and therefore disease onset and progression. Animal models are relevant to investigate the early stage of OA and metabolic changes occurring in joint tissues. The goal of this narrative review is to summarize the scientific data available in the literature on soluble biomarkers in animal models of OA. Design A literature search was conducted using the PubMed/Medline and Scopus databases between February 1995 and December 2015. All original articles, systematic and narrative reviews published in French or in English were considered. Results We summarized the data of 69 studies and proposed a classification scheme for OA biomarkers in animal studies, largely inspired by the BIPEDS classification. Conclusions Studies about biomarkers and animal models indicate that some markers could be valuable to monitor OA progression and assess therapeutic response in some animal models.

Identification of Targets of a New Nutritional Mixture for Osteoarthritis Management Composed by Curcuminoids Extract, Hydrolyzed Collagen and Green Tea Extract.

OBJECTIVE: We have previously demonstrated that a mixture of curcuminoids extract, hydrolyzed collagen and green tea extract (COT) inhibited inflammatory and catabolic mediator's synthesis by osteoarthritic human chondrocytes. The objective of this study was to identify new targets of COT using genomic and proteomic approaches. DESIGN: Cartilage specimens were obtained from 12 patients with knee osteoarthritis. Primary human chondrocytes were cultured in monolayer until confluence and then incubated for 24 or 48 hours in the absence or in the presence of human interleukin(IL)-1ß (10-11M) and with or without COT, each compound at the concentration of 4 µg/ml. Microarray gene expression profiling between control, COT, IL-1ß and COT IL-1ß conditions was performed. Immunoassays were used to confirm the effect of COT at the protein level. RESULTS: More than 4000 genes were differentially expressed between conditions. The key regulated pathways were related to inflammation, cartilage metabolism and angiogenesis. The IL-1ß stimulated chemokine ligand 6, matrix metalloproteinase-13, bone morphogenetic protein-2 and stanniocalcin1 gene expressions and protein productions were down-regulated by COT. COT significantly decreased stanniocalcin1 production in basal condition. Serpin E1 gene expression and protein production were down-regulated by IL-1ß. COT reversed the inhibitory effect of IL-1ß. Serpin E1 gene expression was up-regulated by COT in control condition. CONCLUSION: The COT mixture has beneficial effect on osteoarthritis physiopathology by regulating the synthesis of key catabolic, inflammatory and angiogenesis factors. These findings give a scientific rationale for the use of these natural ingredients in the management of osteoarthritis.

Gene expression pattern of cells from inflamed and normal areas of osteoarthritis synovial membrane.

OBJECTIVE: To compare the gene expression patterns of synovial cells from inflamed or normal/reactive areas of synovial membrane obtained from the same patient with osteoarthritis (OA). METHODS: At the time of total knee replacement, synovial tissues were obtained from 12 patients with knee OA. The inflammation status of the synovial membrane was characterized according to macroscopic criteria and classified as normal/reactive or inflamed. Biopsy samples were cultured separately for 7 days. Microarray gene expression profiling was performed on normal/reactive and inflamed areas. Western blot and immunohistochemistry were used to confirm the identified genes that were differentially expressed. RESULTS: We identified 896 genes that were differentially expressed between normal/reactive and inflamed areas. The key pathways were related to inflammation, cartilage metabolism, Wnt signaling, and angiogenesis. In the inflammation network, the genes TREM1 and S100A9 were strongly up-regulated. The genes MMP3, MMP9, CTSH (cathepsin H), and CTSS (cathepsin S) were significantly up-regulated in the cartilage catabolism pathway, while the most up-regulated anabolism enzyme gene was HAS1. In the Wnt signaling pathway, the genes for Wnt-5a and low-density lipoprotein receptor-related protein 5 were up-regulated, while the gene FZD2 and the gene for Dkk-3 were down-regulated. Finally, STC1, which codes for a protein involved in angiogenesis, was identified as the most up-regulated gene in inflamed compared with normal/reactive areas. CONCLUSION: This study is the first to identify different expression patterns between 2 areas of the synovial membrane from the same patient. These differences concern several key pathways involved in OA pathogenesis. This analysis also provides information regarding new genes and proteins as potential targets of treatment.

Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis.

Synovitis is a key feature in osteoarthritis and is associated with symptom severity. Synovial membrane inflammation is secondary to cartilage degradation which occurs in the early stage and is located adjacent to cartilage damage. This inflammation is characterized by the invasion and activation of macrophages and lymphocytes, the release in the joint cavity of large amounts of pro-inflammatory and procatabolic mediators, and by a local increase of synovial membrane vascularity. This latter process plays an important role in the chronicity of the inflammatory reaction by facilitating the invasion of the synovium by immune cells. Therefore, synovial membrane angiogenesis represents a key target for the treatment of osteoarthritis. This paper is a narrative review of the literature referenced in PubMed during the past 5 years. It addresses in particular three questions. What are the mechanisms involved in synovium blood vessels invasion? Are current medications effective in controlling blood vessels formation and invasion? What are the perspectives of research in this area?

Importance of synovitis in osteoarthritis: evidence for the use of glycosaminoglycans against synovial inflammation.

OBJECTIVES: After detailing the different aspects of synovial inflammation (i.e., cellular, biochemical, and vascular) and based on the current knowledge, the aim of this review was to collect the available in vitro and in vivo data regarding the potency of some glycosaminoglycan (GAG) compounds to target synovial inflammation, an important aspect of osteoarthritis. METHODS: The first part of the review corresponds to a qualitative review of the inflammatory status of OA synovial membrane. The second part corresponds to a systematic review of the literature regarding the potential effects of some GAGs on the previously described phenomenon. RESULTS: The synovial aspect of the inflammatory status of OA has been detailed. Chondroitin sulfate has demonstrated to control the three aspects of synovial membrane inflammation: cell infiltration and activity, biochemical mediators release, and angiogenesis. Glucosamine is also active on both cellular and molecular aspects of the inflammatory reaction. Hyaluronic acid seems to be anti-inflammatory in its native form, while products of degradation are reported to be pro-angiogenic. CONCLUSION: Much evidence suggests that some of the studied GAG compounds could target different aspects of synovitis. Some of them could be considered in combination therapy since they exhibit complementary properties. Most of the studies have concentrated on articular cartilage and chondrocytes. In order to achieve a structure modification, one may now consider all joint tissues and investigate the drug potency on all of them. Potent treatment should trigger the most important features of OA: cartilage degradation, subchondral bone sclerosis, and all aspects of synovial inflammation.

A role for the canonical nuclear factor-κB pathway in coupling neurotrophin-induced differential survival of developing spiral ganglion neurons.

Neurotrophins are key players of neural development by controlling cell death programs. However, the signaling pathways that mediate their selective responses in different populations of neurons remain unclear. In the mammalian cochlea, sensory neurons differentiate perinatally into type I and II populations both expressing TrkB and TrkC, which bind respectively brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). How these two neuronal populations respond differentially to these two neurotrophins remains unknown. Here, we report in rat the segregation of the nuclear factor-κB (NFκB) subunit p65 specifically within the type II population postnatally. Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFκB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea. Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons. Taken together, these results identify NFκB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons.