TGFβ1 induces hypertrophic change and expression of angiogenic factors in human chondrocytes

Chen, Jielin; Zou, Chang; Chen, Yunfang; Zhu, Weimin; Liu, Wei; Huang, Jianghong; Liu, Qisong; Wang, Daming; Li, Duan; Xiong, Jianyi; Cui, Jiaming; Jia, Zhaofeng; Wang, Daping

doi:10.18632/oncotarget.20509

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…Targeting the transforming growth factor β1 (TGF-β1) or relevant receptors may help to prevent or lessen angiogenic activity in OA. One group of researchers has reported that TGF-β1 treatment of human chondrocytes cultured in vitro significantly upregulates genes involved in chondrocyte hypertrophy and blood vessel development [ 55 ]. Another potential strategy for attenuating angiogenic activity in OA cartilage is to target chondromodulin-I (ChM-I) expression [ 56 ].…”

Section: Targeting Oa Cartilagementioning

confidence: 99%

Implications of Angiogenesis Involvement in Arthritis

MacDonald

Liu

et al. 2018

IJMS

156

117

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Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases.

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Section: Targeting Oa Cartilagementioning

confidence: 99%

Implications of Angiogenesis Involvement in Arthritis

MacDonald

Liu

et al. 2018

IJMS

156

117

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“… 44 To address this issue, we also utilized nasal septal cartilage derived chondrocytes, a hyaline cartilage source, free of osteoarthritis, which confirmed the pro-angiogenic capacity of hyaline cartilage. To exclude a possible effect of TGFβ in the pro-angiogenic behaviour of the tissue engineered constructs, 21 we also tested CM derived from the native cartilage tissue and demonstrated that both releasates induce a pro-angiogenic response. This effect was independent of the source of the tissue, as we tested both human nasal cartilage as well as bovine articular cartilage and when compared to previously published data it has a similarly pro-angiogenic effect as d21 chondrogenically differentiated.…”

Section: Discussionmentioning

confidence: 99%

“… 16 Interestingly, VEGFa is not only expressed in OA cartilage but also in mature healthy cartilage and chondrocyte-derived tissue-engineered constructs 17 - 19 that will not be invaded by blood vessels. A pro-angiogenic potential of cartilage has been observed in experiments with chondrocytes forming networks in vitro in Matrigel 20 , 21 and with conditioned medium of cultured chondrocytes on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation in vitro .…”

Section: Introductionmentioning

confidence: 99%

The Releasate of Avascular Cartilage Demonstrates Inherent Pro-Angiogenic Properties In Vitro and In Vivo

et al. 2021

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Objective Cartilage is avascular and numerous studies have identified the presence of single anti- and pro-angiogenic factors in cartilage. To better understand the maintenance hyaline cartilage, we assessed the angiogenic potential of complete cartilage releasate with functional assays in vitro and in vivo. Design We evaluated the gene expression profile of angiogenesis-related factors in healthy adult human articular cartilage with a transcriptome-wide analysis generated by next-generation RNAseq. The effect on angiogenesis of the releasate of cartilage tissue was assessed with a chick chorioallantoic membrane (CAM) assay as well as human umbilical vein endothelial cell (HUVEC) migration and proliferation assays using conditioned media generated from tissue-engineered cartilage derived from human articular and nasal septum chondrocytes as well as explants from bovine articular cartilage and human nasal septum. Experiments were done with triplicate samples of cartilage from 3 different donors. Results RNAseq data of 3 healthy human articular cartilage donors revealed that the majority of known angiogenesis-related factors expressed in healthy adult articular cartilage are pro-angiogenic. The releasate from generated cartilage as well as from tissue explants, demonstrated at least a 3.1-fold increase in HUVEC proliferation and migration indicating a pro-angiogenic effect of cartilage. Finally, the CAM assay demonstrated that cartilage explants can indeed attract vessels; however, their ingrowth was not observed. Conclusion Using multiple approaches, we show that cartilage releasate has an inherent pro-angiogenic capacity. It remains vessel free due to anti-invasive properties associated with the tissue itself.

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“…A previous study has also reported that the TGF-β signaling pathway can promote angiogenesis in endothelial progenitor cells by upregulating VEGF expression ( 23 ). Moreover, it has been shown that TGF-β1 induces angiogenesis in cartilage of OA ( 9 , 19 ). Collectively, it was speculated that the TIMP3/TGF-β1 axis may be involved in chondrocyte degeneration and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study has reported that transforming growth factor (TGF)-β1 signaling is a pivotal mediator in cartilage injury and OA development ( 8 ). Moreover, TGF-β1 may induce ECM mineralization, cell hypertrophy and angiogenesis, thus accelerating cartilage degeneration ( 9 ). Smad2/3, as essential downstream molecules of the TGF-β1 pathway, can induce tissue inhibitor of matrix metalloproteinase-3 (TIMP3) expression in human chondrocytes ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

TIMP3/TGF‑β1 axis regulates mechanical loading‑induced chondrocyte degeneration and angiogenesis

Zhao

Liu

2020

Mol Med Rep

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chondrocytes in injured cartilage tissue are susceptible to mechanical loading; mechanical overloading can induce cartilage degeneration. The aim of the present study was to investigate whether mechanical loading can regulate chondrocyte degeneration and angiogenesis via the tissue inhibitor of matrix metalloproteinase-3 (TiMP3)/transforming growth factor (TGF)-β1 axis. Primary human chondrocytes were obtained from knee articular cartilage of a healthy donor. Then, normal chondrocytes or TiMP3 lentivirus-transfected (lV-TiMP3) chondrocytes were subjected to mechanical loading (10 MPa compression). Then, chondrocytes were stimulated with 1 µg/ml lipopolysaccharide (lPS) or treated with ldn-193189 (inhibitor of TGF-β1 signaling pathway). in addition, human umbilical vein endothelial cells (HuVecs) were co-cultured with chondrocytes or lV-TiMP3 chondrocytes. The expression levels of collagen-i, proteoglycan, TiMP3, TGF-β1, Smad2 and Smad3 were detected by reverse transcription-quantitative Pcr and western blotting. Moreover, cell apoptosis and viability were determined using flow cytometry and MTT analysis, while cell migration was observed by Transwell assays. in addition, the vascular endothelial growth factor (VeGF)/VeGF receptor (r)2 binding rate in HuVecs was detected by a solid-phase binding assay. it was demonstrated that mechanical loading significantly inhibited the expression levels of collagen-i and proteoglycan in chondrocytes, as well as reducing cell proliferation and promoting cell apoptosis. in addition, the expression levels of TiMP3, TGF-β1, phosphorylated (p)-Smad2 and p-Smad3 were significantly decreased in degenerated chondrocytes that were induced by lPS, as well as in chondrocytes treated with ldn-193189. Furthermore, TiMP3 overexpression suppressed cell migration and reduced the VeGF/VeGFr2 binding rate in HuVecs. Mechanical loading significantly inhibited the expression levels of TiMP3, TGF-β1, p-Smad2 and p-Smad3 in chondrocytes, and also increased cell migration of HuVecs; TGF-β1 treatment or TiMP3 overexpression reversed these effects. Thus, the TiMP3/TGF-β1 axis may be a vital signaling pathway in mechanical loading-induced chondrocyte degeneration and angiogenesis.

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TGFβ1 induces hypertrophic change and expression of angiogenic factors in human chondrocytes

Cited by 13 publications

References 33 publications

Implications of Angiogenesis Involvement in Arthritis

Implications of Angiogenesis Involvement in Arthritis

The Releasate of Avascular Cartilage Demonstrates Inherent Pro-Angiogenic Properties In Vitro and In Vivo

TIMP3/TGF‑β1 axis regulates mechanical loading‑induced chondrocyte degeneration and angiogenesis

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