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Hyaluronic acid-curcumin conjugate suppresses the fibrotic functions of myofibroblasts from contractive joint by the PTGER2 demethylation.

ABSTRACT: Joint contracture is a fibrotic complication induced by joint immobilization and trauma, which is characterized as excessive myofibroblast proliferation in joint capsule. The treatments of joint contracture are unsatisfied and patients are suffered from joint dysfunction. Our previous study has shown that curcumin can inhibit myofibroblast proliferation in vitro, but the major challenge is the low aqueous solubility and biological activity of curcumin. In this study, hyaluronic acid-curcumin (HA-Cur) conjugate was synthesized to suppress myofibroblasts in joint contracture. Cells were isolated from the joint capsules of joint contracture patients and induced to active myofibroblasts by transforming growth factor-? (TGF-?). The anti-fibrotic function and mechanisms of HA-Cur were investigated by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction (PCR), methylation-specific PCR, western blot, transwell migration assay and proliferation assay. Results showed that 30??M HA-Cur significantly attenuated the fibrotic functions of myofibroblast in joint contracture in vitro by regulating the methylation of prostaglandin E receptor 2 (PTGER2) and inhibiting TGF-? signaling. This may provide a mechanism for the treatment of joint contracture, and provide a molecular target PTGER2 for therapy during the pathogenesis of joint contracture.

SUBMITTER: Yu D

PROVIDER: S-EPMC6783700 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Hyaluronic acid-curcumin conjugate suppresses the fibrotic functions of myofibroblasts from contractive joint by the PTGER2 demethylation.

Yu Dongjie D Zhuang Ze Z Ren Jianhua J Hu Xuefeng X Wang Zhe Z Zhang Jieyu J Luo Yuansen Y Wang Kun K He Ronghan R Wang Yunbing Y

Regenerative biomaterials 20190422 5

Joint contracture is a fibrotic complication induced by joint immobilization and trauma, which is characterized as excessive myofibroblast proliferation in joint capsule. The treatments of joint contracture are unsatisfied and patients are suffered from joint dysfunction. Our previous study has shown that curcumin can inhibit myofibroblast proliferation <i>in vitro</i>, but the major challenge is the low aqueous solubility and biological activity of curcumin. In this study, hyaluronic acid-curcu ...[more]

PMID: 31616564

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA

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Dataset Information

Hyaluronic acid-curcumin conjugate suppresses the fibrotic functions of myofibroblasts from contractive joint by the PTGER2 demethylation.

Publications

Hyaluronic acid-curcumin conjugate suppresses the fibrotic functions of myofibroblasts from contractive joint by the PTGER2 demethylation.

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