{"title":"The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis","authors":"Anwesha Mukherjee, Bodhisatwa Das","doi":"10.1016/j.bbiosy.2024.100090","DOIUrl":null,"url":null,"abstract":"<div><p>Osteoarthritis (OA) is a chronic musculoskeletal disorder characterized by an imbalance between (synthesis) and catabolism (degradation) in altered homeostasis of articular cartilage mediated primarily by the innate immune system. OA degenerates the joints resulting in synovial hyperplasia, degradation of articular cartilage with damage of the structural and functional integrity of the cartilage extracellular matrix, subchondral sclerosis, osteophyte formation, and is characterized by chronic pain, stiffness, and loss of function. Inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. In OA apart from catabolic effects, anti-inflammatory anabolic processes also occur continually. There is also an underlying chronic inflammation present, not only in cartilage tissue but also within the synovium, which perpetuates tissue destruction of the OA joint. The consideration of inflammation in OA considers synovitis and/or other cellular and molecular events in the synovium during the progression of OA. In this review, we have presented the progression of joint degradation that results in OA. The critical role of inflammation in the pathogenesis of OA is discussed in detail along with the dysregulation within the cytokine networks composed of inflammatory and anti-inflammatory cytokines that drive catabolic pathways, inhibit matrix synthesis, and promote cellular apoptosis. OA pathogenesis, fluctuation of synovitis, and its clinical impact on disease progression are presented here along with the role of synovial macrophages in promoting inflammatory and destructive responses in OA. The role of interplay between different cytokines, structure, and function of their receptors in the inter-cellular signaling pathway is further explored. The effect of cytokines in the increased synthesis and release of matrix-decomposing proteolytic enzymes, such as matrix metalloproteinase (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS), is elaborated emphasizing the potential impact of MMPs on the chondrocytes, synovial cells, articular and periarticular tissues, and other immune system cells migrating to the site of inflammation. We also shed light on the pathogenesis of OA via oxidative damage particularly due to nitric oxide (NO) via its angiogenic response to inflammation. We concluded by presenting the current knowledge about the tissue inhibitors of metalloproteinases (TIMPs). Synthetic MMP inhibitors include zinc binding group (ZBG), non-ZBG, and mechanism-based inhibitors, all of which have the potential to be therapeutically beneficial in the treatment of osteoarthritis. Improving our understanding of the signaling pathways and molecular mechanisms that regulate the MMP gene expression, may open up new avenues for the creation of therapies that can stop the joint damage associated with OA.</p></div>","PeriodicalId":72379,"journal":{"name":"Biomaterials and biosystems","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666534424000035/pdfft?md5=c37f6194ffd0bc0e6eab89940301458b&pid=1-s2.0-S2666534424000035-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials and biosystems","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666534424000035","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 0
Abstract
Osteoarthritis (OA) is a chronic musculoskeletal disorder characterized by an imbalance between (synthesis) and catabolism (degradation) in altered homeostasis of articular cartilage mediated primarily by the innate immune system. OA degenerates the joints resulting in synovial hyperplasia, degradation of articular cartilage with damage of the structural and functional integrity of the cartilage extracellular matrix, subchondral sclerosis, osteophyte formation, and is characterized by chronic pain, stiffness, and loss of function. Inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. In OA apart from catabolic effects, anti-inflammatory anabolic processes also occur continually. There is also an underlying chronic inflammation present, not only in cartilage tissue but also within the synovium, which perpetuates tissue destruction of the OA joint. The consideration of inflammation in OA considers synovitis and/or other cellular and molecular events in the synovium during the progression of OA. In this review, we have presented the progression of joint degradation that results in OA. The critical role of inflammation in the pathogenesis of OA is discussed in detail along with the dysregulation within the cytokine networks composed of inflammatory and anti-inflammatory cytokines that drive catabolic pathways, inhibit matrix synthesis, and promote cellular apoptosis. OA pathogenesis, fluctuation of synovitis, and its clinical impact on disease progression are presented here along with the role of synovial macrophages in promoting inflammatory and destructive responses in OA. The role of interplay between different cytokines, structure, and function of their receptors in the inter-cellular signaling pathway is further explored. The effect of cytokines in the increased synthesis and release of matrix-decomposing proteolytic enzymes, such as matrix metalloproteinase (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS), is elaborated emphasizing the potential impact of MMPs on the chondrocytes, synovial cells, articular and periarticular tissues, and other immune system cells migrating to the site of inflammation. We also shed light on the pathogenesis of OA via oxidative damage particularly due to nitric oxide (NO) via its angiogenic response to inflammation. We concluded by presenting the current knowledge about the tissue inhibitors of metalloproteinases (TIMPs). Synthetic MMP inhibitors include zinc binding group (ZBG), non-ZBG, and mechanism-based inhibitors, all of which have the potential to be therapeutically beneficial in the treatment of osteoarthritis. Improving our understanding of the signaling pathways and molecular mechanisms that regulate the MMP gene expression, may open up new avenues for the creation of therapies that can stop the joint damage associated with OA.
骨关节炎(OA)是一种慢性肌肉骨骼疾病,其特点是关节软骨的合成(合成)和分解(降解)失衡,主要由先天性免疫系统介导的平衡发生改变。OA 使关节退化,导致滑膜增生、关节软骨退化,软骨细胞外基质的结构和功能完整性受到破坏、软骨下硬化、骨质增生形成,并以慢性疼痛、僵硬和功能丧失为特征。生物力学压力等因素引发的炎症参与了骨关节炎的发展。在 OA 中,除了分解代谢作用外,抗炎合成代谢过程也在不断发生。此外,还有一种潜在的慢性炎症,不仅存在于软骨组织中,也存在于滑膜中,它使 OA 关节的组织破坏持续存在。对 OA 中炎症的研究考虑了在 OA 进展过程中滑膜炎和/或滑膜中的其他细胞和分子事件。在本综述中,我们介绍了导致 OA 的关节退化过程。我们详细讨论了炎症在 OA 发病机制中的关键作用,以及由炎症和抗炎细胞因子组成的细胞因子网络内的失调,这些细胞因子驱动分解代谢途径、抑制基质合成并促进细胞凋亡。本文介绍了 OA 的发病机制、滑膜炎的波动及其对疾病进展的临床影响,以及滑膜巨噬细胞在促进 OA 炎症和破坏性反应中的作用。研究还进一步探讨了细胞因子、结构及其受体功能在细胞间信号传导途径中的相互作用。阐述了细胞因子对基质分解蛋白水解酶(如基质金属蛋白酶(MMPs)和具有血栓软骨素基序的类崩解酶和金属蛋白酶(ADAMTS))合成和释放增加的影响,强调了 MMPs 对软骨细胞、滑膜细胞、关节和关节周围组织以及迁移到炎症部位的其他免疫系统细胞的潜在影响。我们还揭示了氧化损伤,特别是一氧化氮(NO)对炎症的血管生成反应导致的 OA 发病机制。最后,我们介绍了目前有关金属蛋白酶组织抑制剂(TIMPs)的知识。合成的金属蛋白酶抑制剂包括锌结合基团 (ZBG)、非 ZBG 和基于机制的抑制剂,它们都有可能对骨关节炎的治疗有益。随着我们对调控 MMP 基因表达的信号通路和分子机制的了解不断加深,可能会开辟新的治疗途径,从而阻止与 OA 相关的关节损伤。