Search Results (8)

ADAMTS-5 (aggrecanase-2) is a major metalloprotease involved in regulating the cartilage extracellular matrix. Due to its role in removing aggrecan in the progression of osteoarthritis (OA), ADAMTS-5 is often regarded as a potential therapeutic target for OA. Punicalagin (PCG), a polyphenolic ellagitannin found in pomegranate (Punica grunatum L.), and ellagic acid (EA), a hydrolytic metabolite of PCG, have been widely investigated as potential disease-modifying osteoarthritis drugs (DMOADs) due to their potent antioxidant and anti-inflammatory properties, but their interaction with ADAMTS-5 has yet to be determined. In this study, molecular docking simulations were used to predict enzyme–inhibitor binding interactions. The results suggest that both compounds may be able to bind within the active site via the formation of H bonds and interactions between the ligand’s aromatic rings and hydrophobic residue in the enzyme with inhibition constants of 183.3 µM and 1.13 µM for PCG and EA, respectively. Biochemical activity against recombinant human ADAMTS-5 was assessed using a dimethylmethylene blue-based assay to determine residual sulfated glycosaminoglycan (sGAG) in porcine articular cartilage. Although its loss could not be attributed to ADAMTS-5, sGAG was effectively persevered by PCG and EA. The potential conversion of PCG to EA by enzyme-catalyzed hydrolysis activity was then investigated using liquid chromatography–mass spectroscopy to determine the potential for the use of PCG and EA as a prodrug–proactive metabolite pair in the development of drug delivery systems to arthritic synovial joints. Full article

Background/Objectives: Osteoarthritis (OA) is a highly prevalent, degenerative joint disease capable of causing severe pain and impaired mobility. Current treatments mitigate symptoms but do not cure the disease. The development of a disease-modifying osteoarthritis drug (DMOAD) could improve patient outcomes by slowing, halting, or reversing joint damage. Many DMOADs have progressed to clinical trials, but very few have made a significant impact, and none have been approved for clinical use. The purpose of this review is to present an update on the current status of DMOADs with a particular focus on results published since 2010. Methods: A comprehensive search was conducted within PubMed and ClinicalTrials.gov for novel DMOADs enrolled in phase II and III clinical trials between 1 January 2010 and 1 July 2024. Results: Eleven DMOAD candidates are reviewed and critically analyzed for their potential benefit in OA treatment—Lorecivivint (SM04690), TissueGene-C, Cindunistat (SD-6010), Sprifermin, UBX0101, TPX-100, GLPG1972/S201086, Lutikizumab (ABT-981), SAR113945, MIV-711, and LNA043—and relevant challenges to their development are discussed. Conclusions: Six DMOADs have demonstrated statistically significant evidence of a structural or symptomatic benefit without major safety concerns in phase II and III randomized controlled trials post-2010. Full article

Osteoarthritis (OA) is the most common joint disease that causes local inflammation and pain, significantly reducing the quality of life and normal social activities of patients. Currently, there are no disease-modifying OA drugs (DMOADs) available, and treatment relies on pain relief agents or arthroplasty. To address this significant unmet medical need, we aimed to develop monoclonal antibodies that can block the osteoclast-associated receptor (OSCAR). Our recent study has revealed the importance of OSCAR in OA pathogenesis as a novel catabolic regulator that induces chondrocyte apoptosis and accelerates articular cartilage destruction. It was also shown that blocking OSCAR with a soluble OSCAR decoy receptor ameliorated OA in animal models. In this study, OSCAR-neutralizing monoclonal antibodies were isolated and optimized by phage display. These antibodies bind to and directly neutralize OSCAR, unlike the decoy receptor, which binds to the ubiquitously expressed collagen and may result in reduced efficacy or deleterious off-target effects. The DMOAD potential of the anti-OSCAR antibodies was assessed with in vitro cell-based assays and an in vivo OA model. The results demonstrated that the anti-OSCAR antibodies significantly reduced cartilage destruction and other OA signs, such as subchondral bone plate sclerosis and loss of hyaline cartilage. Hence, blocking OSCAR with a monoclonal antibody could be a promising treatment strategy for OA. Full article

Osteoarthritis (OA) affects over 250 million people worldwide and despite various existing treatment strategies still has no cure. It is a multifactorial disease characterized by cartilage loss and low-grade synovial inflammation. Focusing on these two targets together could be the key to developing currently missing disease-modifying OA drugs (DMOADs). This review aims to discuss the latest cell-free techniques applied in cartilage tissue regeneration, since they can provide a more controllable approach to inflammation management than the cell-based ones. Scaffolds, extracellular vesicles, and nanocarriers can be used to suppress inflammation, but they can also act as immunomodulatory agents. This is consistent with the latest tissue engineering paradigm, postulating a moderate, controllable inflammatory reaction to be beneficial for tissue remodeling and successful regeneration. Full article

Osteoarthritis (OA) is a prevalent and debilitating age-related joint disease characterized by articular cartilage degeneration, synovial membrane inflammation, osteophyte formation, as well as subchondral bone sclerosis. OA drugs at present are mainly palliative and do not halt or reverse disease progression. Currently, no disease-modifying OA drugs (DMOADs) are available and total joint arthroplasty remains a last resort. Therefore, there is an urgent need for the development of efficacious treatments for OA management. Among all novel pharmaco-therapeutical options, exosome-based therapeutic strategies are highly promising. Exosome cargoes, which include proteins, lipids, cytokines, and various RNA subtypes, are potentially capable of regulating intercellular communications and gene expression in target cells and tissues involved in OA development. With extensive research in recent years, exosomes in OA studies are no longer limited to classic, mesenchymal stem cell (MSC)-derived vesicles. New origins, structures, and functions of exosomes are constantly being discovered and investigated. This review systematically summarizes the non-classic origins, biosynthesis, and extraction of exosomes, describes modification and delivery techniques, explores their role in OA pathogenesis and progression, and discusses their therapeutic potential and hurdles to overcome in OA treatment. Full article

Osteoarthritis (OA) is the most prevalent degenerative joint disease affecting millions of people worldwide. Currently, clinical nonsurgical treatments of OA are only limited to pain relief, anti-inflammation, and viscosupplementation. Developing disease-modifying OA drugs (DMOADs) is highly demanded for the efficient treatment of OA. As OA is a local disease, intra-articular (IA) injection directly delivers drugs to synovial joints, resulting in high-concentration drugs in the joint and reduced side effects, accompanied with traditional oral or topical administrations. However, the injected drugs are rapidly cleaved. By properly designing the drug delivery systems, prolonged retention time and targeting could be obtained. In this review, we summarize the drugs investigated for OA treatment and recent advances in the IA drug delivery systems, including micro- and nano-particles, liposomes, and hydrogels, hoping to provide some information for designing the IA injected formulations. Full article

Osteoarthritis (OA) of the knee is a disease that significantly decreases the quality of life due to joint deformation and pain caused by degeneration of articular cartilage. Since the degeneration of cartilage is irreversible, intervention from an early stage and control throughout life is important for OA treatment. For the treatment of early OA, the development of a disease-modifying osteoarthritis drug (DMOAD) for intra-articular (IA) injection, which is attracting attention as a point-of-care therapy, is desired. In recent years, the molecular mechanisms involved in OA progression have been clarified while new types of drug development methods based on gene sequences have been established. In addition to conventional chemical compounds and protein therapeutics, the development of DMOAD from the new modalities such as gene therapy and oligonucleotide therapeutics is accelerating. In this review, we have summarized the current status and challenges of DMOAD for IA injection, especially for protein therapeutics, gene therapy, and oligonucleotide therapeutics. Full article

As the most common chronic degenerative joint disease, osteoarthritis (OA) is the leading cause of pain and physical disability, affecting millions of people worldwide. Mainly characterized by articular cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovial inflammation, OA is a heterogeneous disease that impacts all component tissues of the articular joint organ. Pathological changes, and thus symptoms, vary from person to person, underscoring the critical need of personalized therapies. However, there has only been limited progress towards the prevention and treatment of OA, and there are no approved effective disease-modifying osteoarthritis drugs (DMOADs). Conventional treatments, including non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy, are still the major remedies to manage the symptoms until the need for total joint replacement. In this review, we provide an update of the known OA risk factors and relevant mechanisms of action. In addition, given that the lack of biologically relevant models to recapitulate human OA pathogenesis represents one of the major roadblocks in developing DMOADs, we discuss current in vivo and in vitro experimental OA models, with special emphasis on recent development and application potential of human cell-derived microphysiological tissue chip platforms. Full article