Increased Synovial Expression of Transforming Growth Factor (TGF)-β Receptor Endoglin and TGF-β1 in Rheumatoid Arthritis: Possible Interactions in the Pathogenesis of the Disease

doi:10.1006/clin.1995.1114

Clinical Immunology and Immunopathology

Volume 76, Issue 2, August 1995, Pages 187-194

Clinical Immunology ...

https://doi.org/10.1006/clin.1995.1114 Get rights and content

Abstract

The ingress of inflammatory cells into the rheumatoid (RA) synovial tissue (ST) plays a role in the pathogenesis of this disease. Transforming growth factor β (TGF-β) may play a role in this process. We have investigated the distribution of endoglin, a newly described receptor for TGF-β1 and -β3, in RA compared to osteoarthritis (OA) or normal ST. Immunohistochemical analysis was carried out using an anti-TGF-β1 monoclonal antibody (mAb) as well as 10 mAbs raised against various epitopes of endoglin. This study was performed on ST from 10 patients with RA, 10 with OA, and 4 normal individuals. TGF-β1 expression was significantly up-regulated on RA compared to OA and normal ST lining cells, interstitial macrophages, and endothelial cells (P < 0.05). All anti-endoglin mAbs uniformly reacted with endothelial cells in RA, OA, and normal STs. However, 3 out of 10 anti-endoglin mAbs reacted with significantly more RA versus normal ST lining cells (P < 0.05), as well as RA compared to OA and normal macrophages (P < 0.05). There was a positive correlation between TGF-β1 and endoglin reactivity on the synovial lining layer and subsynovial macrophages (P < 0.05). These results indicate that TGF-β1 and certain epitopes of endoglin, a TGF-β1 and -β3 receptor, are up-regulated on myeloid elements in RA compared to normal ST. Endoglin is also present on ST endothelia, and its expression may also be increased on OA compared to normal ST lining cells. These findings implicate endoglin in the pathogenesis of RA.

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Citation Excerpt :
On the other hand, TGF-β1 is one of the most powerful and widely distributed profibrogenic mediators in the body. A previous research has indicated enhanced expression of TGF-β1 protein in RA synovial, and it may be related with active pathological changes in RA synovia including synoviocyte hyperplasia, inflammatory cell infiltration and granuloma formation (Dai et al., 2000; Szekanecz et al., 1995). In addition, data from other reports have shown that systemic inhibition of TGF-β1 signalling can significantly reduce the severity of synovitis in RA animal models, likely by suppressing TGF-β1-mediated synoviocytes proliferation and endothelial angiogenesis (Sakuma et al., 2007; Wahl et al., 1993).
Discovering novel compounds with higher activities is a key aim of natural products research. Gardenia jasminoides Ellis is a herb with anti-inflammatory properties. Iridoid glycosides (mainly geniposide) and crocetin derivatives (crocins) are the two major active constituents in this herb and are considered its active ingredients. However, which components are responsible for the anti-inflammatory properties of gardenia have remained to be investigated.
Here, we prepared total iridoid glycocides (TIG) and total crocins (TC) from G. jasminoides Ellis, determined their main chemical constituents, and performed animal studies to evaluate their anti-adjuvant arthritis activities, thus, proposing a reasonable mechenism to explain the anti-inflammatory activities of the active components in this herbal remedy.
TIG and TC were prepared by using HPD-100 macroporous resin, and characterized by UHPLC-DAD-MS and UV–Vis spectrophotometer. Then, freund's complete adjuvant-injected rats underwent drug treatments with TIG (160 mg/kg) and TC (160 mg/kg) for 14 days, and their ankle diameters were measured. Moreover, X-ray radiographs of the adjuvant injected hind paws were evaluated. Finally, histopathological examinations of the ankle joints, spleens and thymus were carried out to evaluate inflammatory reactions, and immunohistochemical measurements were conducted to evaluate TNF-α and TGF-β1 expression in the ankle joint of the rats.
The chemical composition determination of the current study showed that TIG was mainly composed of geniposide and TC was a fraction predominantly with crocin-1, crocin-2 and crocin-3. Calculation of results showed that TIG and TC contained 58.2% total iridoid glycosides and 54.7% total crocins, respectively. Our study suggested TIG and TC treatments markedly decreased paw swelling and ankle diameters of AA rats (both p < 0.05). The radiological analysis showed that administration of TIG and TC ameliorated bone destruction, and reduced the radiological bone destruction scores (TIG p < 0.05, TC p>0.05). Moreover, data from histological assessment demonstrated considerable mitigation of inflammation in the joints (both p < 0.01), spleen and thymus of AA rats treated with TIG and TC. TNF-α and TGF-β1 protein expression according to immunohistochemistry staining also supported the anti-arthritis activities of TIG and TC (TNF-α: TIG p < 0.01 and TC p < 0.05, TGF-β1: TIG p < 0.01 and TC p>0.05).
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Citation Excerpt :
Some studies would support the idea of that endoglin and ALK-1 participate in a common signaling pathway and endoglin would potentiate TGF-β/ALK-1 signaling through a direct association of ALK-1 with the cytoplasmic and extracellular domain of endoglin [121]. Endoglin is highly expressed in vascular endothelial cells at sites of active angiogenesis, during embryogenesis [140,141], in healing wounds and inflammation processes [101,142], upon vascular injury [143], and in cancer [136,144–146]. It has also been described to be overexpressed after ischemia and reperfusion in kidney, heart or hindlimbs [102,147,148].
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In this review, we would like to offer a complete vision of the role of ALK-1 in many process related to cardiovascular homeostasis, and the involvement of this protein in the development of cardiovascular diseases, suggesting the possibility of using the ALK-1/smad-1 pathway as a powerful therapeutic target.

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Regular ArticleIncreased Synovial Expression of Transforming Growth Factor (TGF)-β Receptor Endoglin and TGF-β1 in Rheumatoid Arthritis: Possible Interactions in the Pathogenesis of the Disease

Abstract

Regular Article
Increased Synovial Expression of Transforming Growth Factor (TGF)-β Receptor Endoglin and TGF-β1 in Rheumatoid Arthritis: Possible Interactions in the Pathogenesis of the Disease