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      Disease-modifying therapeutic strategies in osteoarthritis: current status and future directions

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          Abstract

          Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.

          Osteoarthritis: moving from symptom relief towards disease control

          Researchers are exploring several promising avenues to develop treatments for osteoarthritis that control or reverse its progress, rather than simply relieving the symptoms of inflammation and pain. These new opportunities are emerging from increased understanding of the molec_reular mechanisms underlying the onset and progression of osteoarthritis. Seung-Baik Kang, Jin-Hong Kim and colleagues at Seoul National University, South Korea, review the current status and future directions of disease-modifying strategies that are already showing promise in clinical trials. They discuss approaches aimed at restricting the damage to joint cartilage by controlling the inflammatory signaling molecules, enzyme actions and molecular pathways that cause cartilage to degenerate. They also consider treatments that could stimulate the active regeneration of damaged cartilage. They conclude that some approaches will soon be ready to move into general clinical use.

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          Most cited references146

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          Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

          The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
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            Osteoarthritis.

            Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.
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              Central sensitization: a generator of pain hypersensitivity by central neural plasticity.

              Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
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                Author and article information

                Contributors
                ssbkang@snu.ac.kr
                jinhkim@snu.ac.kr
                Journal
                Exp Mol Med
                Exp Mol Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                30 November 2021
                30 November 2021
                November 2021
                : 53
                : 11
                : 1689-1696
                Affiliations
                [1 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Biological Sciences, College of Natural Sciences, , Seoul National University, ; Seoul, 08826 South Korea
                [2 ]GRID grid.410720.0, ISNI 0000 0004 1784 4496, Center for RNA Research, , Institute for Basic Science, ; Seoul, 08826 South Korea
                [3 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Business Administration, Business School, , Seoul National University, ; Seoul, 08826 South Korea
                [4 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Orthopaedic Surgery, , Seoul National University College of Medicine, Boramae Hospital, ; Seoul, 07061 South Korea
                [5 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Interdisciplinary Program in Bioinformatics, , Seoul National University, ; Seoul, 08826 South Korea
                Author information
                http://orcid.org/0000-0002-4788-3141
                http://orcid.org/0000-0003-1966-1397
                http://orcid.org/0000-0001-6489-1832
                http://orcid.org/0000-0002-6480-1929
                Article
                710
                10.1038/s12276-021-00710-y
                8640059
                34848838
                6ef6cae4-c8ae-4ad3-97f6-7ee86f3b6a9b
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 February 2021
                : 18 August 2021
                : 22 September 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: NRF-2020R1A2C2012300
                Award ID: NRF-2016R1A5A1010764
                Award ID: NRF-2017M3A9D8064193
                Award ID: NRF-2021R1I1A1A01059252
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003621, Ministry of Science, ICT and Future Planning (MSIP);
                Award ID: IBS-R008-D1
                Award Recipient :
                Funded by: Suh Kyungbae foundation
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2021

                Molecular medicine
                osteoarthritis,translational research
                Molecular medicine
                osteoarthritis, translational research

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