Aggrecan and COMP Improve Periosteal Chondrogenesis by Delaying Chondrocyte Hypertrophic Maturation

Caron, M.M.; Janssen, M; Peeters, Laura; Haudenschild, Dominik R.; Cremers, A.; Surtel, D.A.; Rhijn, Lodewijk W. van; Emans, Pieter J.; Welting, Tim J. M.

doi:10.3389/fbioe.2020.01036

Cited by 27 publications

(18 citation statements)

References 47 publications

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“…Previous studies have also ascertained that in the progression of OA, COMP expression in the early and late stages in various parts of cartilage, shows discrepancy [ 164 ], which may be explained as COMP’s attempt to repair the damaged cartilage. COMP can enhance chondrogenic differentiation of human bone marrow stem cells [ 165 ]. In addition, COMP can be used as a marker of OA, RA, and a variety of fibrotic diseases.…”

Section: Adamts and Cartilage Degeneration In Oamentioning

confidence: 99%

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

Peng

et al. 2022

Biomolecules

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Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of cartilage function. Factors, including diet, age, and obesity, impact and/or lead to osteoarthritis. In the past few years, OA has received considerable scholarly attention owing to its increasing prevalence, resulting in a cumbersome burden. At present, most of the interventions only relieve short-term symptoms, and some treatments and drugs can aggravate the disease in the long run. There is a pressing need to address the safety problems due to osteoarthritis. A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats (ADAMTS) metalloproteinase is a kind of secretory zinc endopeptidase, comprising 19 kinds of zinc endopeptidases. ADAMTS has been implicated in several human diseases, including OA. For example, aggrecanases, ADAMTS-4 and ADAMTS-5, participate in the cleavage of aggrecan in the extracellular matrix (ECM); ADAMTS-7 and ADAMTS-12 participate in the fission of Cartilage Oligomeric Matrix Protein (COMP) into COMP lyase, and ADAMTS-2, ADAMTS-3, and ADAMTS-14 promote the formation of collagen fibers. In this article, we principally review the role of ADAMTS metalloproteinases in osteoarthritis. From three different dimensions, we explain how ADAMTS participates in all the following aspects of osteoarthritis: ECM, cartilage degeneration, and synovial inflammation. Thus, ADAMTS may be a potential therapeutic target in osteoarthritis, and this article may render a theoretical basis for the study of new therapeutic methods for osteoarthritis.

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Section: Adamts and Cartilage Degeneration In Oamentioning

confidence: 99%

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

Peng

et al. 2022

Biomolecules

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“…At the cellular level, we could show that both COMP and TSP-4 supported the synthesis and matrix deposition of collagen II, IX, XII and proteoglycans, while inhibiting those of collagen I and collagen X. The modulating effect of COMP has also been described before, showing that the addition of COMP or aggrecan suppresses the expression of hypertrophic genes in periosteal chondrocytes [ 59 ]. The increased expression of the main ECM components, collagen II and proteoglycans, as well as their potential to enhance TGF-β1 induced collagen II and proteoglycan synthesis, strongly suggest an involvement of both proteins in cartilage repair by restoring an ECM composition that maintains original tensile strength and elasticity [ 1 ].…”

Section: Discussionmentioning

confidence: 66%

COMP and TSP-4: Functional Roles in Articular Cartilage and Relevance in Osteoarthritis

Maly

Sastre

Farrell

et al. 2021

IJMS

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Osteoarthritis (OA) is a slow-progressing joint disease, leading to the degradation and remodeling of the cartilage extracellular matrix (ECM). The usually quiescent chondrocytes become reactivated and accumulate in cell clusters, become hypertrophic, and intensively produce not only degrading enzymes, but also ECM proteins, like the cartilage oligomeric matrix protein (COMP) and thrombospondin-4 (TSP-4). To date, the functional roles of these newly synthesized proteins in articular cartilage are still elusive. Therefore, we analyzed the involvement of both proteins in OA specific processes in in vitro studies, using porcine chondrocytes, isolated from femoral condyles. The effect of COMP and TSP-4 on chondrocyte migration was investigated in transwell assays and their potential to modulate the chondrocyte phenotype, protein synthesis and matrix formation by immunofluorescence staining and immunoblot. Our results demonstrate that COMP could attract chondrocytes and may contribute to a repopulation of damaged cartilage areas, while TSP-4 did not affect this process. In contrast, both proteins similarly promoted the synthesis and matrix formation of collagen II, IX, XII and proteoglycans, but inhibited that of collagen I and X, resulting in a stabilized chondrocyte phenotype. These data suggest that COMP and TSP-4 activate mechanisms to protect and repair the ECM in articular cartilage.

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“…Furthermore, our RT-qPCR revealed that only V602I significantly upregulated SOX9, and the RNAseq data showed that SOX9 had a smaller fold change compared to other chondrogenic genes, such as GDF5, COL6A1, COL6A3, and COMP. In fact, these genes, which were upregulated in V620I-and T89I-hiPSC-derived chondrocytes, have a pro-chondrogenic but anti-hypertrophic phenotype (Caron et al, 2020;Chu et al, 2017;Hecht & Sage, 2006). Therefore, these results suggest additional and alternative pathways to FST and SOX9 that are responsible for the V620I and T89I skeletal dysplasias.…”

Section: Trpv4 Mutations Suppress Chondrocyte Hypertrophy 26mentioning

confidence: 89%

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Dicks

Maksaev²,

Harissa

et al. 2021

Preprint

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Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.

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Aggrecan and COMP Improve Periosteal Chondrogenesis by Delaying Chondrocyte Hypertrophic Maturation

Cited by 27 publications

References 47 publications

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

COMP and TSP-4: Functional Roles in Articular Cartilage and Relevance in Osteoarthritis

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

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