Upregulation of HSP47 and Collagen Type III in the Dermal Fibrotic Disease, Keloid

Naitoh, Motoko; Hosokawa, Nobuko; Kubota, Hiroshi; Tanaka, Toshinori; Shirane, Hirofumi; Sawada, Masashi; Nishimura, Yoshihiko; Nagata, Kazuhiro

doi:10.1006/bbrc.2001.4257

Cited by 99 publications

(99 citation statements)

References 25 publications

(30 reference statements)

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“…In a study involving biopsies obtained from keloids, increased steady-state levels of HSP47 mRNA were associated with increased numbers of HSP47-immunoreactive fibroblasts. 7 In contrast, following balloon injury to rat carotid arteries, HSP47 mRNA increased for up to 7 days after injury before declining to control levels at 14 days, while the abundance of HSP47-positive cells in the expanding neointima increased between days 7 and 14. 30 Observations made using in situ hybridization in carbon tetrachloride-treated rat livers are also relevant to this question.…”

Section: Discussionmentioning

confidence: 80%

“…1 Although the precise role of HSP47 in the processing of procollagens has not been established, 2,3 expression of HSP47 is increased in fibrotic human lung, kidney and skin [4][5][6][7] and in animal models of lung, kidney and liver fibrosis. [8][9][10][11] Recent studies have suggested that levels of procollagen gene expression and rates of procollagen synthesis are regulated coordinately with HSP47.…”

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confidence: 99%

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Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver

Brown

Broadhurst

Mathahs

et al. 2005

Laboratory Investigation

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HSP47 is a collagen-specific chaperone that is required for normal collagen synthesis. In animal models of liver injury, hepatic stellate cells (HSC) have been identified as a source of HSP47. Because expression of HSP47 has not been investigated in human liver, the aim of these studies was to characterize expression of HSP47 in human liver and to investigate its regulation in human HSC in vitro. Immunohistochemistry demonstrated staining for HSP47 along the sinusoids of normal and cirrhotic human livers and in fibrous septa. Dual fluorescence confocal microscopy showed colocalization of HSP47 with synaptophysin, a marker for HSC. Levels of immunoreactive HSP47 and its transcript tended to be higher in cirrhotic livers than in normal livers. The abundance of HSP47 protein was unchanged by treatment of cultured human HSC with TGF-b1, angiotensin II, hypoxia and a number of other treatments intended to increase collagen synthesis. A modest reduction in HSP47 was achieved by transfection with antisense oligonucleotides and was associated with a significant decrease in procollagen synthesis. These observations suggest that HSP47 is constitutively expressed in human HSC and that HSP47 may be a target for antifibrotic therapy.

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver

Brown

Broadhurst

Mathahs

et al. 2005

Laboratory Investigation

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“…Preliminary scanning of the promoter region of both collagen type I a1, COL1A1, and collagen type III a1, COL3A1, revealed some putative Stat3 binding sites (CP Lim and X Cao, unpublished). It will be interesting to investigate whether Stat3 has a direct effect on the transcription of procollagen type I and III, the two collagens that are found to be highly synthesized in keloids (Abergel et al, 1985;Naitoh et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment and management of keloid scars have been difficult, owing to their recurrence, and although a myriad of treatments are available none are fully effective (Tuan and Nichter, 1998;Alster and Tanzi, 2003;Mustoe, 2004). Keloid scars are typified by overexuberant deposition of collagen and other ECM components such as fibronectin by keloid fibroblasts (KFs) (Diegelmann et al, 1979;Babu et al, 1989), with overproduction of collagen types I and III mRNA in keloid tissues (Naitoh et al, 2001). Keloid fibroblasts reportedly displayed an increased rate of proliferation upon wounding (Calderon et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.

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“…Although expression of Hsp47 is up-regulated by various cytosolic stresses, including heat shock, constitutive expression of Hsp47 correlates with that of collagen in various organs and collagen-related pathophysiological conditions, including liver fibrosis, connective tissue diseases, and dermal fibrotic diseases (24,25). A recent study showed that TGF-␤, a pro-fibrotic cytokine, regulates Hsp47 production in fibroblast cell lines (26).…”

mentioning

confidence: 99%

Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

Kawasaki

Ushioda

Ito

et al. 2015

Journal of Biological Chemistry

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Background: Although knockdown of heat shock protein 47 (Hsp47) attenuates liver fibrosis, the underlying molecular mechanism is unknown. Results: Deletion of Hsp47 caused activated hepatic stellate cells (HSCs) to undergo ER stress-mediated apoptosis when autophagy was inhibited. Conclusion: ER stress-induced apoptosis may underlie the clearance of collagen-producing HSCs. Significance: Hsp47 could be an attractive therapeutic target for fibrosis treatment.

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Upregulation of HSP47 and Collagen Type III in the Dermal Fibrotic Disease, Keloid

Cited by 99 publications

References 25 publications

Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver

Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

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