Transglutaminase 2 in cartilage homoeostasis: novel links with inflammatory osteoarthritis

Adamczyk, Magdalena

doi:10.1007/s00726-016-2305-1

Cited by 8 publications

(4 citation statements)

References 83 publications

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“…Transglutaminase 2 (TG2) is a 78-kDa calcium-dependent enzyme of the protein-glutamine γ-glutamyl-transferase family 5 , 6 . In the presence of calcium, TG2 functions as a catalytic enzyme that modifies the protein-bound glutamine side chains, resulting in protein crosslinking through transamidation or deamidation 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Han

Jung

Kim

et al. 2020

Sci Rep

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Transglutaminase 2 (TG2), also known as tissue transglutaminase, is a calcium-dependent enzyme that has a variety of intracellular and extracellular substrates. TG2 not only increases in osteoarthritis (OA) tissue but also affects the progression of OA. However, it is still unclear how TG2 affects cartilage degradation in OA at the molecular level. Surgically induced OA lead to an increase of TG2 in the articular cartilage and growth plate, and it was dependent on TGFβ1 in primary chondrocytes. The inhibition of TG2 enzymatic activity with intra-articular injection of ZDON, the peptide-based specific TG2 inhibitor, ameliorated the severity of surgically induced OA as well as the expression of MMP-3 and MMP-13. ZDON attenuated MMP-3 and MMP-13 expression in TGFβ- and calcium ionophore-treated chondrocytes in a Runx2-independent manner. TG2 inhibition with ZDON suppressed canonical Wnt signaling through a reduction of β-catenin, which was mediated by ubiquitination-dependent proteasomal degradation. In addition, TG2 activation by a calcium ionophore enhanced the phosphorylation of AMPK and FoxO3a and the nuclear translocation of FoxO3a, which was responsible for the increase in MMP-13. In conclusion, TG2 plays an important role in the pathogenesis of OA as a major catabolic mediator that affects the stability of β-catenin and FoxO3a-mediated MMP-13 production.

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Section: Introductionmentioning

confidence: 99%

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Han

Jung

Kim

et al. 2020

Sci Rep

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“…[47][48][49][50][51][52] These findings further suggest similarity in activity between the rhFGF18 protein and AAV2-FGF18 gene therapy, regardless of the differences in delivery modality. Conversely, TGM2, a calciumdependent acyltransferase with observed involvement in cartilage homeostasis, 53 and SERPINA1, which has previously been associated with chondrogenesis and chondrocyte differentiation, 54 require further investigation. Pathway analysis and mechanistic studies may help elucidate whether the differences can be attributed to the degree of hFGF18 accumulation in the cytoplasm, delivery, or pathways activated by the AAV2 capsid.…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism

Hollander

Goraltchouk²,

Rawal

et al. 2023

CARTILAGE

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Objective To determine the characterization of chondrogenic properties of adeno-associated virus type 2 (AAV2)-delivered hFGF18, via analysis of effects on primary human chondrocyte proliferation, gene expression, and in vivo cartilage thickness changes in the tibia and meniscus. Design Chondrogenic properties of AAV2-FGF18 were compared with recombinant human FGF18 (rhFGF18) in vitro relative to phosphate-buffered saline (PBS) and AAV2-GFP negative controls. Transcriptome analysis was performed using RNA-seq on primary human chondrocytes treated with rhFGF18 and AAV2-FGF18, relative to PBS. Durability of gene expression was assessed using AAV2-nLuc and in vivo imaging. Chondrogenesis was evaluated by measuring weight-normalized thickness in the tibial plateau and the white zone of the anterior horn of the medial meniscus in Sprague-Dawley rats. Results AAV2-FGF18 elicits chondrogenesis by promoting proliferation and upregulation of hyaline cartilage–associated genes, including COL2A1 and HAS2, while downregulating fibrocartilage-associated COL1A1. This activity translates to statistically significant, dose-dependent increases in cartilage thickness in vivo within the area of the tibial plateau, following a single intra-articular injection of the AAV2-FGF18 or a regimen of 6 twice-weekly injections of rhFGF18 protein relative to AAV2-GFP. In addition, we observed AAV2-FGF18-induced and rhFGF18-induced increases in cartilage thickness of the anterior horn of the medial meniscus. Finally, the single-injection AAV2-delivered hFGF18 offers a potential safety advantage over the multi-injection protein treatment as evidenced by reduced joint swelling over the study period. Conclusion AAV2-delivered hFGF18 represents a promising strategy for the restoration of hyaline cartilage by promoting extracellular matrix production, chondrocyte proliferation, and increasing articular and meniscal cartilage thickness in vivo after a single intra-articular injection.

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“…In absence of TG2, FXIIIA fails to undergo chondrocyte hypertrophy [208]. The conjunction of plasma membranebound TG2 and FXIIIA with a raised expression of FXIIIA upregulates the p38 MAP kinase signaling pathway in chondrocytes of OA cartilage in situ [209]. In turn, p38 signaling sig-nificantly increases SOX-9, which inhibits both in vitro and in vivo chondrocyte maturation to hypertrophy by DP-MSC-induced chondrogenesis [210].…”

Section: Engineered Chondrogenesis By D-mscsmentioning

confidence: 99%

Chondrogenic Potential of Dental-Derived Mesenchymal Stromal Cells

et al. 2021

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The field of tissue engineering has revolutionized the world in organ and tissue regeneration. With the robust research among regenerative medicine experts and researchers, the plausibility of regenerating cartilage has come into the limelight. For cartilage tissue engineering, orthopedic surgeons and orthobiologists use the mesenchymal stromal cells (MSCs) of various origins along with the cytokines, growth factors, and scaffolds. The least utilized MSCs are of dental origin, which are the richest sources of stromal and progenitor cells. There is a paradigm shift towards the utilization of dental source MSCs in chondrogenesis and cartilage regeneration. Dental-derived MSCs possess similar phenotypes and genotypes like other sources of MSCs along with specific markers such as dentin matrix acidic phosphoprotein (DMP) -1, dentin sialophosphoprotein (DSPP), alkaline phosphatase (ALP), osteopontin (OPN), bone sialoprotein (BSP), and STRO-1. Concerning chondrogenicity, there is literature with marginal use of dental-derived MSCs. Various studies provide evidence for in-vitro and in-vivo chondrogenesis by dental-derived MSCs. With such evidence, clinical trials must be taken up to support or refute the evidence for regenerating cartilage tissues by dental-derived MSCs. This article highlights the significance of dental-derived MSCs for cartilage tissue regeneration.

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Transglutaminase 2 in cartilage homoeostasis: novel links with inflammatory osteoarthritis

Cited by 8 publications

References 83 publications

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism

Chondrogenic Potential of Dental-Derived Mesenchymal Stromal Cells

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