TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

Dietz, Harry C.

doi:10.1172/jci42014

Cited by 108 publications

(95 citation statements)

References 40 publications

(23 reference statements)

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“…TGFb, a central molecule in the pathogenesis of Marfan aortopathy 12,14,[32][33][34] , and its downstream signalling pathways (canonical pSmad2 (ref. 35) and non-canonical pERK1/2 (ref.…”

Section: Resultsmentioning

confidence: 99%

“…Recent advancements in understanding mechanisms of aortic disease have stemmed from hallmark studies in the genetically fragile Marfan aorta, which have shown that transforming growth factor b (TGFb) and its downstream intracellular kinase signalling pathways play a central role in the pathogenesis [12][13][14] . In contrast, an inflammatory pathway is thought to be a major component of aortic conditions in the atherosclerotic/ degenerative aorta seen in the typical elderly patient 15,16 .…”

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confidence: 99%

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Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

et al. 2015

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Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM-CSF) is a triggering molecule for this condition. Transcription factor Krüppel-like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

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“…TGFb, a central molecule in the pathogenesis of Marfan aortopathy 12,14,[32][33][34] , and its downstream signalling pathways (canonical pSmad2 (ref. 35) and non-canonical pERK1/2 (ref.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

et al. 2015

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“…TSP-1 is a key regulator of TGF-β1 activation, and losartan has been shown to reduce TSP-1 expression and TGF-β1 activation in mouse models of Marfan's syndrome and muscular dystrophy (19). The measurement of protein levels in homogenized HSTS26T tumors showed that losartan did not affect total TGF-β1 levels but significantly reduced TSP-1, active TGF-β1, and collagen I levels (Fig.…”

Section: Losartan Inhibits Collagen I Synthesis By Carcinoma-associatedmentioning

confidence: 89%

“…Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (15,16). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1)-mediated down-regulation of TGF-β1 activators such as thrombospondin-1 (TSP-1) (15)(16)(17)(18)(19). Using a dose that has minimal effects on mean arterial blood pressure (MABP), we show that losartan reduces collagen I levels in four tumor models-a spontaneous mouse mammary carcinoma (FVB MMTV PyVT), an orthotopic pancreatic adenocarcinoma (L3.6pl), and s.c. implanted fibrosarcoma (HSTS26T) and melanoma (Mu89).…”

mentioning

confidence: 99%

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

Diop-Frimpong

Chauhan

Krane

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

610

559

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The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan-a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity-can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. drug delivery | matrix modifier | thrombospondin-1 | transforming growth factor β | transport A lthough nanotherapeutics have offered new hope for cancer treatment, their clinical efficacy is modest (1-4). This is partly because their penetration is hindered, especially in fibrotic tumors, where the small interfibrillar spacing in the interstitium retards the movement of particles larger than 10 nm (5-8). Pegylated liposomal doxorubicin (Doxil), approved by the Food and Drug Administration, and oncolytic viruses, currently in multiple clinical trials, represent two nanotherapeutics whose size (∼100 nm) hinders their intratumoral distribution and therapeutic effectiveness (9). Matrix modifiers such as bacterial collagenase, relaxin, and matrix metalloproteinase-1 and -8 have been used to modify the collagen or proteoglycan network in tumors and have improved the efficacy of intratumorally (i.t.) injected oncolytic viruses (8,(10)(11)(12)(13). However, these agents may produce normal tissue toxicity (e.g., bacterial collagenase) or increase the risk of tumor progression (e.g., relaxin, matrix metalloproteinases).Losartan (14)-approved to control hypertension in patients -does not have many of these safety risks. Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (15, 16). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1)-mediated down-regulation of TGF-β1 activators such as thrombospondin-1 (TSP-1) (15-19). Using a dose that has minimal effects on mean arterial blood pressure (MABP), we show that losartan reduces collagen I levels in four tumor models-a spontaneous mouse mammary carcinoma (FVB MMTV PyVT), an orthotopic pancreatic adenocarcinoma (L3.6pl), and s.c. implanted fibrosarcoma (HSTS26T) and melanoma (Mu89). Losartan also improves the intratumoral penetration of nanoparticles injected i.t. or i.v.Based on these results, we tested how losartan would affect the distributi...

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“…However, histological and biochemical assessment of aortic tissue derived from patients affected by LDS, or mouse models, show a paradoxical signature of high TGF-b signaling (van de Laar et al 2011;Lindsay et al 2012;Gallo et al 2014). These contrasting observations have generated controversy in the field regarding the specific role of TGF-b in the initiation and progression of aneurysm (Lavoie et al 2005;Dietz 2010;Mallat and Daugherty 2015). Various mechanisms have been proposed to explain how LDS mutations can paradoxically result in increased TGF-b signaling in vivo, including the possibility that angiotensin II receptor signaling, rather than TGF-b signaling, might be responsible for the observed increase in Smad2 and Smad3 phosphorylation and upregulation of TGF-b-driven gene products , or that different intrinsic susceptibility to LDS-causing mutations in cells of different type or embryonic origin might result in paracrine signaling overdrive caused by excessive secretion of TGF-b1 ligand (Lindsay and Dietz 2011).…”

Section: Loeys -Dietz Syndromementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

Cited by 108 publications

References 40 publications

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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