Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis

Kim, Ju‐Ryoung; Yoo, Jong Jin; Kim, Hyun Ah

doi:10.3390/ijms19030674

Cited by 89 publications

(79 citation statements)

References 114 publications

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“…The pathology of KOA is complex and involves numerous factors, including genetic predisposition (14,15), altered mechanical loading (16) and inflammation (17). Although the key processes leading to OA remain unclear, the death of chondrocytes and the loss of extracellular matrix are considered to be important features of the degeneration of articular cartilage in OA (18).…”

Section: Introductionmentioning

confidence: 99%

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

Feng

Wang

et al. 2020

Int J Mol Med

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Knee osteoarthritis (KOA) is a major cause of leg disability in the elderly population. Recently, the expression levels of circulating microRNA (miRNA) let-7e have been reported to be significantly reduced in KOA. The aims of the present study were to assess the feasibility of let-7e as a serum marker for detecting KOA and to explore the underlying mechanisms of its involvement. Based on previous studies and bioinformatics analysis, let-7e may regulate apoptosis and autophagy of articular chondrocytes. A total of 10 patients with KOA and 10 patients with trauma without KOA were recruited to examine the levels of let-7e in peripheral blood. Subsequently, KOA rat models were established, and the levels of let-7e in the cartilage and serum were examined, the expression of apoptotic proteins and autophagy-related proteins in the cartilage were investigated, and apoptotic and autophagic activities of primary cultured chondrocytes were also detected. In patients with KOA, let-7e levels in the peripheral serum were significantly decreased compared with the control group, and this result was confirmed in the peripheral serum and cartilage of KOA rats. In addition, the expression levels of proteins involved in the apoptotic pathway were increased in the cartilage of KOA rats, and apoptotic activity was increased. The expression of autophagy-related proteins beclin 1 and microtubule associated protein 1 light chain 3 β (Lc3B) II/Lc3BI in the articular cartilage of KOA rats was lower compared with the controls, and autophagy was decreased. Si-Miao-San (SMS) treatment restored the expression of let-7e and reversed the changes in apoptosis and autophagy. Therefore, the present study provided additional evidence that circulating let-7e may be a potential serum biomarker for the diagnosis and treatment of KOA. Elevated apoptosis levels and decreased autophagy levels of cartilage tissue are involved in KOA, and treatment with SMS may reverse these effects.

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Section: Introductionmentioning

confidence: 99%

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

Feng

Wang

et al. 2020

Int J Mol Med

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“…But, beyond proteoglycan′s viscoelasticity, little is known about its other functions. In OA, the ECM containing proteoglycan is decreased [ 42 ], and abnormalities in endochondral ossification, as well as reduction in viscoelasticity, have been reported [ 16 ]. Therefore, in this study, we applied sPG to cells at multiple stages of endochondral ossification to investigate possible novel cartilage regulatory functions for proteoglycan, which goes beyond its role in cartilage viscoelasticity.…”

Section: Discussionmentioning

confidence: 99%

Exogenous Application of Proteoglycan to the Cell Surface Microenvironment Facilitates to Chondrogenic Differentiation and Maintenance

Masutani

Yamada

Hara

et al. 2020

IJMS

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Osteoarthritis (OA), a disease that greatly impacts quality of life, has increasing worldwide prevalence as the population ages. However, its pathogenic mechanisms have not been fully elucidated and current therapeutic treatment strategies are inadequate. In recent years, abnormal endochondral ossification in articular cartilage has received attention as a pathophysiological mechanism in OA. Cartilage is composed of abundant extracellular matrix components, which are involved in tissue maintenance and regeneration, but how these factors affect endochondral ossification is not clear. Here, we show that the application of aggrecan-type proteoglycan from salmon nasal cartilage (sPG) exhibited marked proliferative capacity through receptor tyrosine kinases in chondroprogenitor cells, and also exhibited differentiation and three-dimensional structure formation via phosphorylation of Insulin-like Growth Factor-1 Receptor and Growth Differentiation Factor 5 expression. Furthermore, sPG inhibited calcification via expression of Runx2 and Col10 (factors related to induction of calcification), while increasing Mgp, a mineralization inhibitory factor. As a result of analyzing the localization of sPG applied to the cells, it was localized on the surface of the cell membrane. In this study, we found that sPG, as a biomaterial, could regulate cell proliferation, differentiation and calcification inhibition by acting on the cell surface microenvironment. Therefore, sPG may be the foundation for a novel therapeutic approach for cartilage maintenance and for improved symptoms in OA.

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“…Module analysis demonstrated that the development of OA synovitis is associated with ‘cytokine-cytokine receptor interactions’, ‘NOD-like receptor signaling pathway’, ‘Toll-like receptor signaling pathway’. Previous studies have demonstrated that the occurrence and development of OA were associated with a number of cytokines, leading to synovial inflammation, cartilage damage and osteophyte production ( 30 , 49 ). The present study demonstrated that OA synovial inflammation is associated with ‘NOD-like receptor signaling pathway’, ‘Toll-like receptor signaling pathway’ and ‘TNF signaling pathway’, and OA progression is additionally associated with ‘osteoclast differentiation’.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis to identify key genes and pathways influencing synovial inflammation in osteoarthritis

Lin

Wu²,

Zhao

et al. 2018

Mol Med Report

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Osteoarthritis (OA) is a chronic arthropathy that occurs in the middle-aged and elderly population. The present study aimed to identify gene signature differences between synovial cells from OA synovial membrane with and without inflammation, and to explain the potential mechanisms involved. The differentially expressed genes (DEGs) between 12 synovial membrane with inflammation and 12 synovial membrane without inflammation from the dataset GSE46750 were identified using the Gene Expression Omnibus 2R. The DEGs were subjected to enrichment analysis, protein-protein interaction (PPI) analysis and module analysis. The analysis results were compared with text-mining results. A total of 174 DEGs were identified. Gene Ontology enrichment results demonstrated that functional molecules encoded by the DEGs primarily had extracellular location, molecular functions predominantly involving ‘chemokine activity’ and ‘cytokine activity’, and were associated with biological processes, including ‘inflammatory response’ and ‘immune response’. The Kyoto Encyclopedia of Genes and Genomes results demonstrated that DEGS may function through pathways associated with ‘rheumatoid arthritis’, ‘chemokine signaling pathway’, ‘complement and coagulation cascades’, ‘TNF signaling pathway’, ‘intestinal immune networks for IgA production’, ‘cytokine-cytokine receptor interaction’, ‘allograft rejection’, ‘Toll-like receptor signaling pathway’ and ‘antigen processing and presentation’. The top 10 hub genes [interleukin (IL)6, IL8, matrix metallopeptidase (MMP)9, colony stimulating factor 1 receptor, FOS proto-oncogene, AP1 transcription factor subunit, insulin-like growth factor 1, TYRO protein tyrosine kinase binding protein, MMP3, cluster of differentiation (CD)14 and CD163] and four gene modules were identified from the PPI network using Cytoscape. In addition, text-mining was used to identify the commonly used drugs and their targets for the treatment of OA. It was initially verified whether the results of the present study were useful for the study of OA treatment targets and pathways. The present study provided insight for the molecular mechanisms of OA synovitis. The hub genes and associated pathways derived from analysis may be targets for OA treatment. IL8 and MMP9, which were validated by text-mining, may be used as molecular targets for the OA treatment, while other hub genes require further validation.

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Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis

Cited by 89 publications

References 114 publications

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

Exogenous Application of Proteoglycan to the Cell Surface Microenvironment Facilitates to Chondrogenic Differentiation and Maintenance

Bioinformatics analysis to identify key genes and pathways influencing synovial inflammation in osteoarthritis

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