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Background. Osteoarthritis is a common chronic disease characterized by progressive degradation of all joint components and inflammation. The priority issue in the management of OA is searching for drugs that simultaneously relieve symptoms, modify the course of the disease, and are safe for use. Symptomatic slow-acting drugs (SYSADOA) are of considerable interest due to their potential to slow cartilage degeneration and potential osteoarthritis disease modifying effect. The purpose of the study was to analyze current literature data on several types of SYSADOA, their biological role, mechanisms of effect on joints, effectiveness and safetye. Materials and methods. An analytical review of literature data was conducted using the analysis of scientific databases PubMed, Web of Science, Scopus, Google Scholar for the period 2005–2024, the search was conducted using the keywords “osteoarthritis”, “SYSADOA”, “DMOAD”, “effectiveness”, “safety”. Results. Glucosamine salts (GA) and chondroitin sulfate (CS) are the most studied slow-acting drugs and have positive biological effects on joint tissues. Prescription salts of GA and CS have effect of pain relieve and joint function improvement as separate agents and also potentiate the effect in combination. Studies revealed limiting of cartilage volume loss and joint space narrowing – a potential DMOAD effect of these drugs. GA salts and CS drugs are safe, as they have no difference in the frequency of side effects compared to placebo. The quality of drugs largely depends on the type of raw materials and technological production process, which are not standardized now. Conclusions. The role of SYSADOA in the treatment of OA has not been definitively determined, and studies on the effectiveness of drugs such as SYSADOA and the study of their DMOAD effect are still ongoing. Further studies should focus on the use of pharmacological class SYSADOA that have been properly purified and quality strictly supervised. [ABSTRACT FROM AUTHOR]

Pentosan polysulfate (PPS), a small semi-synthetic highly sulfated heparan sulfate (HS)-like molecule, shares many of the interactive properties of HS. The aim of this review was to outline the potential of PPS as an interventional therapeutic protective agent in physiological processes affecting pathological tissues. PPS is a multifunctional molecule with diverse therapeutic actions against many disease processes. PPS has been used for decades in the treatment of interstitial cystitis and painful bowel disease, it has tissue-protective properties as a protease inhibitor in cartilage, tendon and IVD, and it has been used as a cell-directive component in bioscaffolds in tissue engineering applications. PPS regulates complement activation, coagulation, fibrinolysis and thrombocytopenia, and it promotes the synthesis of hyaluronan. Nerve growth factor production in osteocytes is inhibited by PPS, reducing bone pain in osteoarthritis and rheumatoid arthritis (OA/RA). PPS also removes fatty compounds from lipid-engorged subchondral blood vessels in OA/RA cartilage, reducing joint pain. PPS regulates cytokine and inflammatory mediator production and is also an anti-tumor agent that promotes the proliferation and differentiation of mesenchymal stem cells and the development of progenitor cell lineages that have proven to be useful in strategies designed to effect repair of the degenerate intervertebral disc (IVD) and OA cartilage. PPS stimulates proteoglycan synthesis by chondrocytes in the presence or absence of interleukin (IL)-1, and stimulates hyaluronan production by synoviocytes. PPS is thus a multifunctional tissue-protective molecule of potential therapeutic application for a diverse range of disease processes. [ABSTRACT FROM AUTHOR]

[Display omitted] Osteoarthritis (OA) is a joint disease common worldwide. Currently, no disease-modifying osteoarthritis drugs (DMOADs) have successfully passed clinical trials, often due to a lack of cartilage penetration. Thus, targeting the extracellular matrix (ECM) is a major priority. The design of cartilage-targeting drug delivery systems (DDSs) for intra-articular administration requires consideration of the physicochemical properties of articular cartilage, such as its porosity and negative fixed charge. Various positively charged biomaterials such as polyaminoacids, proteins, polymers, and lipids can be used as DDSs to enhance cartilage penetration. Cationic nanocarriers interact electrostatically with anionic glycosaminoglycans of the ECM, ensuring passive cartilage-targeting penetration and prolonged retention. Active targeting strategies involve DDSs surface decoration using antibodies or peptides with a strong affinity for collagen II and chondrocytes in the cartilage. This review presents all the relevant bio-physicochemical properties of healthy and OA cartilages, as well as state-of-the-art intra-articular cartilage-targeted DDSs, intending to better understand the recent advances in the application of cartilage-targeting delivery systems for OA therapy. [ABSTRACT FROM AUTHOR]

Background: In a previous report, we have identified the cannabinoid receptor 2 (CB2) agonist HU308 to possess a beneficial effect in preventing age and trauma-induced osteoarthritis (OA) in mice. The effects of HU308 were largely related to the capacity of this compound to induce cartilage anabolism which was dependent on the CREB/SOX9 axis, and exhibited pro-survival and pro-proliferative hallmarks of articular cartilage following treatment. Here, we utilized the novel cannabinoid-fenchone CB2 agonists (1B, 1D), which were previously reported to render anti-inflammatory effects in a zymosan model. Methods: Initially, we assessed the selectivity of CB2 using a Gs-protein receptor cAMP potency assay, which was also validated for antagonistic effects dependent on the Gi-protein receptor cAMP pathway. Based on EC50 values, 1D was selected for a zymosan inflammatory pain model. Next, 1D was administered in two doses intra-articularly (IA), in a post-traumatic medial meniscal tear (MMT, Lewis rats) model, and compared to sham, vehicle, and a positive control consisting of fibroblast growth factor 18 (FGF18) administration. The histopathological assessment was carried out according to the Osteoarthritis Research Society International (OARSI) guidelines for rat models following 28 days post-MMT. Results: The G protein receptor assays confirmed that both 1B and 1D possess CB2 agonistic effects in cell lines and in chondrocytes. Co-administering a CB2 antagonists to 25 mg/kg 1D in a paw inflammatory pain model abolished 1D-related anti-swelling effect and partially abolishing its analgesic effects. Using an MMT model, the high dose (i.e., 24 µg) of 1D administered via IA route, exhibited reduced cartilage damage. Particularly, this dose of 1D exhibited a 30% improvement in cartilage degeneration (zonal/total tibial scores) and lesion depth ratios (44%), comparable to the FGF18 positive control. Synovitis scores remained unaffected and histopathologic evaluation of subchondral bone damage did not suggest that 1D treatment changed the load-bearing ability of the rats. Contrary to the anabolic effect of FGF18, synovial inflammation was observed and was accompanied by increased osteophyte size. Conclusion: The structural histopathological analysis supports a disease-modifying effect of IA-administered 1D compound without any deleterious effects on the joint structure. [ABSTRACT FROM AUTHOR]

This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by pathogenic organisms obviating the need for dietary antibiotic supplementation, a practice which has been used to maintain animal productivity but which has led to the emergence of antibiotic resistant bacteria that are passed up the food chain to humans. Seaweed xylan-based animal foodstuffs have been developed to eliminate ruminant green-house gas emissions by gut methanogens in ruminant animals, contributing to atmospheric pollution. Biotransformation of pentosan polysulfate by the gut microbiome converts this semi-synthetic sulfated disease-modifying anti-osteoarthritic heparinoid drug to a prebiotic metabolite that promotes gut health, further extending the therapeutic profile and utility of this therapeutic molecule. Xylans are prominent dietary cereal components of the human diet which travel through the gastrointestinal tract as non-digested dietary fibre since the human genome does not contain xylanolytic enzymes. The gut microbiota however digest xylans as a food source. Xylo-oligosaccharides generated in this digestive process have prebiotic health-promoting properties. Engineered commensal probiotic bacteria also have been developed which have been engineered to produce growth factors and other bioactive factors. A xylan protein induction system controls the secretion of these compounds by the commensal bacteria which can promote gut health or, if these prebiotic compounds are transported by the vagal nervous system, may also regulate the health of linked organ systems via the gut–brain, gut–lung and gut–stomach axes. Dietary xylans are thus emerging therapeutic compounds warranting further study in novel disease prevention protocols. [ABSTRACT FROM AUTHOR]

This review highlights the attributes of pentosan polysulfate (PPS) in the promotion of intervertebral disc (IVD) repair processes. PPS has been classified as a disease-modifying osteoarthritic drug (DMOAD) and many studies have demonstrated its positive attributes in the countering of degenerative changes occurring in cartilaginous tissues during the development of osteoarthritis (OA). Degenerative changes in the IVD also involve inflammatory cytokines, degradative proteases, and cell signaling pathways similar to those operative in the development of OA in articular cartilage. PPS acts as a heparan sulfate (HS) mimetic to effect its beneficial effects in cartilage. The IVD contains small cell membrane HS proteoglycans (HSPGs) such as syndecan, and glypican and a large multifunctional HS/chondroitin sulfate (CS) hybrid proteoglycan (HSPG2/perlecan), that have important matrix-stabilizing properties and sequester, control, and present growth factors from the FGF, VEGF, PDGF, and BMP families to cellular receptors to promote cell proliferation, differentiation, and matrix synthesis. HSPG2 also has chondrogenic properties and stimulates the synthesis of extracellular matrix (ECM) components and expansion of cartilaginous rudiments, and has roles in matrix stabilization and repair. Perlecan is a perinuclear and nuclear proteoglycan (PG) in IVD cells with roles in chromatin organization and control of transcription factor activity, immunolocalizes to stem cell niches in cartilage, promotes escape of stem cells from quiescent recycling, differentiation and attainment of pluripotency and migratory properties. These participate in tissue development and morphogenesis, ECM remodeling and repair. PPS also localizes in the nucleus of stromal stem cells, promotes development of chondroprogenitor cell lineages, ECM synthesis and repair and discal repair by resident disc cells. The availability of recombinant perlecan and PPS offers new opportunities in repair biology. These multifunctional agents offer welcome new developments in repair strategies for the IVD. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteoarthritis is an incurable chronic disease. For this reason, new therapies are constantly emerging to improve clinical signs and the quality of life of our pets. Chondroitin sulfate, glucosamine and hyaluronic acid have been proven effective and are the most widely used in many formulations. In the present study, adding native type II collagen to the combination of chondroitin sulfate, glucosamine and hyaluronic acid showed improvements on osteoarthritis progression in an experimental model of osteoarthritis induced by transection of the cranial cruciate ligament of the knee in New Zealand white rabbits. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone. Overall, our results showed that adding native type II collagen to a combination of glycosaminoglycans allows a significantly slower osteoarthritis progression, compared to glycosaminoglycans alone. A prospective, experimental, randomized, double blinded study was designed to evaluate the effects of glycosaminoglycans, with or without native type II collagen (NC), in an osteoarthritis model induced by cranial cruciate ligament transection. The following compounds were tested: chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), hyaluronic acid (HA) and NC. Fifty-four female 12-week-old New Zealand rabbits were classified into three groups: CTR (control–no treatment), CGH (CS + GlHCl + HA) and CGH-NC (CS + GlHCl + HA + NC). Each group was subdivided into three subgroups according to survival times of 24, 56 and 84 days. Over time, all rabbits developed degenerative changes associated with osteoarthritis. CGH-NC showed significantly improved values on macroscopic evaluation, compared to CTR and CGH. Microscopically, significantly better results were seen with CGH and CGH-NC, compared to CTR, and synovial membrane values were significantly better with CGH-NC compared to CGH. A significant improvement in magnetic resonance imaging biomarkers was also observed with CGH-NC in cartilage transversal relaxation time (T2) and subchondral bone D2D fractal dimension in the lateral condyle. In conclusion, our results show beneficial effects on joint health of CGH and CGH-NC and also supports that adding NC to CGH results in even greater efficacy. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic, debilitating disease affecting millions of people worldwide. Management of OA involves pharmacological and non-pharmacological approaches. Conventional pharmacological treatments have limited efficacy and are associated with a number of side-effects, restricting the number of patients who can use them. New pharmacological therapies for managing OA are required and a number have been developed targeting different tissues in OA: bone and cartilage, synovium and nerves. However, there has been overall limited success. Disease-modifying osteoarthritis drugs (DMOADs) are a putative class of therapies aimed at improving OA structural pathologies and consequent symptoms. Recent DMOAD studies have demonstrated some promising therapies but also provided new considerations for future trials. [ABSTRACT FROM AUTHOR]

One possible approach to treat osteoarthritis (OA) is to counteract cartilage degeneration with anabolic compounds that stimulate chondrocyte proliferation and/or extracellular matrix (ECM) production. Several molecules including sprifermin (recombinant human fibroblast growth factor [FGF18]), insulin‐like growth factor‐1 [IGF1] and ‐2 [IGF2], C‐type natriuretic peptide [CNP], and bone metamorphic protein 7 [BMP7] have been shown to have these characteristics both in vitro and in vivo. However, it is not known how these molecules compare each other regarding their effect on phenotype and stimulation of ECM production in primary chondrocytes. The effects of sprifermin, IGF1, IGF2, CNP, and BMP7 were evaluated on bovine articular chondrocytes, first in monolayer to determine their effective concentrations, and then in three‐dimensional (3D) culture at concentrations of 100 ng/ml for sprifermin; 300 ng/ml for IGF1, IGF2, and BMP7; and 10 nM for CNP. In 3D culture, the effects of a permanent exposure or a cyclic exposure consisting of 24 h incubation per week with the compounds were evaluated. All growth factors increased ECM production and cell proliferation to a similar extent but CNP had almost no effect on bovine chondrocytes. Sprifermin was more effective with cyclic exposure, IGF1, and IGF2 with permanent exposure, and BMP7 showed similar results with both exposures. Regarding the cell phenotype, sprifermin appeared to be the only compound favoring the chondrocyte phenotype; it decreased type I collagen expression and had no hypertrophic effect. Together, these results confirmed that sprifermin is a promising disease‐modifying OA drug. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:653–662, 2020 [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a big burden of disease worldwide and one of the most common causes of disability in the adult population. Currently applied therapies consist of physical therapy, oral medication, intra-articular injections, and surgical interventions, with the main goal being to reduce pain and improve function and quality of life. Intra-articular (IA) administration of drugs has potential benefits in OA treatment because it minimizes systemic bioavailability and side effects associated with oral administration of drugs without compromising the therapeutic effect in the joint. However, IA drug residence time is short and there is a clinical need for a vehicle that is able to provide a sustained release long enough for IA therapy to fulfill its promise. This review summarizes the use of different polymeric systems and the incorporated drugs for IA drug delivery in the osteoarthritic joint with a primary focus on clinical needs and opportunities. [ABSTRACT FROM AUTHOR]

Abstract: Osteoarthritis (OA) is a disease of the joints that affects several million individuals worldwide. This disease, which involves mainly the diarthrodial joints, is chronic and develops slowly over decades, making it very difficult to precisely identify the different etiological and risk factors that influence its onset. At present, most therapies for OA are symptomatic. This review will focus on new OA therapeutics in development that are directed toward pain relief as well as others with the potential to reduce or stop the progression of the disease (DMOADs). This article is part of a Special Issue entitled “Osteoarthritis”. [Copyright &y& Elsevier]

Osteoarthritis (OA) is a disease of the entire joint. Different treatment strategies for OA have been proposed and tested clinically without the desired efficacy. One reason for the scarcity of current chondroprotective agents may be the insufficient understanding of the patho-physiology of the joint and whether the joint damage is reversible or irreversible. In this review, we compile emerging data on cellular and pathological aspects of OA, and ask whether these data could give clue to when cartilage degradation is reversible and whether a point-of-no-return exists. We highlight different stages of OA, and speculate whether different intervention strategies (e.g. DMOAD vs. SMOADs) may only be efficacious at distinct stages of OA. [ABSTRACT FROM AUTHOR]

Abstract: Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model. [Copyright &y& Elsevier]

Abstract: Till date, the pharmaceutical industry has failed to bring effective and safe disease modifying osteoarthritic drugs (DMOADs) to the millions of patients suffering from this serious and deliberating disease. We provide a review of recent data reported on the investigation of DMOADs in clinical trials, including compounds inhibiting matrix-metalloproteinases (MMPs), bisphosphonates, cytokine blockers, calcitonin, inhibitors of inducible nitric oxide synthase (iNOS), doxycycline, glucosamine, and diacereine. We discuss the challenges associated with the drug development process in general and with DMOADs in particular, and we advance the need for a new development paradigm for DMOADs. Two central elements in this paradigm are a stronger focus on the biology of the joint and the application of new and more sensitive biomarkers allowing redesign of clinical trials in osteoarthritis. [Copyright &y& Elsevier]