Lumican promotes joint fibrosis through TGF‐β signaling

Xiao, Dahai; Tang, Liang; Zhuang, Ze-Hao; He, Ronghan; Ren, Jianhua; Jiang, Shihai; Zhu, Lei; Wang, Kun; Shi, Dongquan

doi:10.1002/2211-5463.12974

Cited by 19 publications

(11 citation statements)

References 44 publications

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“… 12 , 13 Moreover, lumican was found to be one of the most regulated proteins in HCM, and studies in non‐cardiac tissues indicate a role for lumican in development of fibrosis. 11 , 14 , 15 , 16 Despite this, lumican has not yet been examined in HCM in detail at the molecular level. Therefore, we have studied the production and localization of lumican in myectomy samples from patients with HOCM, hearts from the well‐established Myh6 R403Q mouse model of HCM and human foetal cardiac fibroblasts (hfCFBs) treated with lumican, with special focus on relationship to collagen.…”

Section: Introductionmentioning

confidence: 99%

“…The SLRP lumican, specifically, is increased in patients with heart failure 10,11 and is shown to be important for heart failure progression and survival during studies of lumican knockout mice 12,13 . Moreover, lumican was found to be one of the most regulated proteins in HCM, and studies in non‐cardiac tissues indicate a role for lumican in development of fibrosis 11,14–16 . Despite this, lumican has not yet been examined in HCM in detail at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

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Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

et al. 2022

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Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8-10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Results Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R 2 = 0.60, P < 0.01) and III (R 2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R 2 = 0.28, P = 0.05) and interstitial (R 2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (À15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer (À8.9%, P < 0.001) collagen fibres. Conclusions The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

et al. 2022

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“…However, biglycan deficiency could also accelerate the IDD process [ 31 ], implying its pleiotropic role in homeostasis and the degenerative process. Lumican facilitates collagen fibril fusion and may accelerate joint fibrosis through TGF-β activation in joint synovial fibroblast [ 32 ]. Increase in fibronectin and its fragments has been linked to IDD and its fibrotic-like events [ 21 , 25 , 26 ].…”

Section: Matrices In Np Fibrosismentioning

confidence: 99%

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

Sun

Lyu

et al. 2022

IJMS

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A growing body of evidence in humans and animal models indicates an association between intervertebral disc degeneration (IDD) and increased fibrotic elements in the nucleus pulposus (NP). These include enhanced matrix turnover along with the abnormal deposition of collagens and other fibrous matrices, the emergence of fibrosis effector cells, such as macrophages and active fibroblasts, and the upregulation of the fibroinflammatory factors TGF-β1 and IL-1/-13. Studies have suggested a role for NP cells in fibroblastic differentiation through the TGF-βR1-Smad2/3 pathway, inflammatory activation and mechanosensing machineries. Moreover, NP fibrosis is linked to abnormal MMP activity, consistent with the role of matrix proteases in regulating tissue fibrosis. MMP-2 and MMP-12 are the two main profibrogenic markers of myofibroblastic NP cells. This review revisits studies in the literature relevant to NP fibrosis in an attempt to stratify its biochemical features and the molecular identity of fibroblastic cells in the context of IDD. Given the role of fibrosis in tissue healing and diseases, the perspective may provide new insights into the pathomechanism of IDD and its management.

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“…To date, there are few in vitro options that are suitable to study myofibroblastogenesis, and these utilize fibroblasts derived from unknown sources, 16,17 cells from human tissues not associated with the local knee environment, 18 knee fibroblasts isolated from animals, 19 or primary cells isolated from the human knee environment with only partial phenotypic characterization. [20][21][22][23][24] Therefore, a well-characterized cell culture model for in vitro myofibroblastogenesis based on primary cultures of knee fibroblasts is essential for controlled experimentation to investigate arthrofibrotic processes at cellular, molecular, and biochemical levels. Such a model would aid in the definition of fibrosis associated pathways unique to the knee tissue, the identification of potential diagnostic markers, and the development of therapeutic options for future in vivo animal and human studies.…”

Section: Introductionmentioning

confidence: 99%

“…However, in vivo models of arthrofibrosis are costly, and the ability to control specific regulatory molecular pathways that contribute to the disease process is limited. To date, there are few in vitro options that are suitable to study myofibroblastogenesis, and these utilize fibroblasts derived from unknown sources, 16,17 cells from human tissues not associated with the local knee environment, 18 knee fibroblasts isolated from animals, 19 or primary cells isolated from the human knee environment with only partial phenotypic characterization 20–24 . Therefore, a well‐characterized cell culture model for in vitro myofibroblastogenesis based on primary cultures of knee fibroblasts is essential for controlled experimentation to investigate arthrofibrotic processes at cellular, molecular, and biochemical levels.…”

Section: Introductionmentioning

confidence: 99%

Human outgrowth knee fibroblasts from patients undergoing total knee arthroplasty exhibit a unique gene expression profile and undergo myofibroblastogenesis upon TGFβ1 stimulation

Bayram

Thaler

Bettencourt

et al. 2022

J of Cellular Biochemistry

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Arthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasties (TKAs). Currently, treatment options are limited. Therefore, an in vitro model of knee-related myofibroblastogenesis is valuable to facilitate investigation of the arthrofibrotic process, diagnostic and therapeutic options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissues from the knees of four patients undergoing primary TKAs for osteoarthritis. From these tissues, we isolated primary cells by the outgrowth method and subsequently characterized these cells in the absence and presence of the pro-myofibroblastic cytokine, transforming growth factor beta 1 (TGFβ1). Light microscopy of knee outgrowth cells revealed spindle-shaped cells, and immunofluorescence (IF) analysis demonstrated staining for the fibroblast-specific markers TE-7 and vimentin (VIM). These knee outgrowth fibroblasts differentiated readily into myofibroblasts as reflected by enhanced α-smooth muscle actin (ACTA2) mRNA and protein expression and increased mRNA expression of collagen type 1 (COL1A1) and type 3 (COL3A1) with collagenous matrix deposition in the presence of TGFβ1.Outgrowth knee fibroblasts were more sensitive to TGFβ1-mediated myofibroblastogenesis than adipose-derived mesenchymal stromal/stem cells (MSCs). While outgrowth knee fibroblasts isolated from three anatomical regions in four patients exhibited similar gene expression, these cells are distinct from other fibroblastic cell types (i.e., Dupuytren's fibroblasts) as revealed by RNA-sequencing. In conclusion, our study provides an in vitro myofibroblastic model of outgrowth knee fibroblasts derived from patients undergoing

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Lumican promotes joint fibrosis through TGF‐β signaling

Cited by 19 publications

References 44 publications

Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

Human outgrowth knee fibroblasts from patients undergoing total knee arthroplasty exhibit a unique gene expression profile and undergo myofibroblastogenesis upon TGFβ1 stimulation

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