tretinoin and Scleroderma--Systemic

Systemic sclerosis and morphea are connective tissue diseases characterized by tightening, thickening, and hardening of the skin, leading to significant morbidity. Unfortunately, current treatment options have limited efficacy for many patients. Cutaneous manifestations of these diseases arise from excess collagen deposition and fibrosis in the skin, through pathogenic mechanisms which have yet to be extensively detailed at the causal immune and cellular levels. Research elucidating the mechanism of action of retinoic acid on collagen production in the skin and case series highlighting the success of retinoic acid on the skin manifestations of systemic sclerosis and on morphea demonstrate its promise as a treatment. Herein they will briefly review the treatment options for both systemic sclerosis and morphea, and will discuss the potential of retinoic acid as a therapy and the supporting evidence from the literature, highlighting the previously published basic science and clinical studies investigating the role of retinoic acid in the treatment of sclerotic skin diseases.

Topics: Dermatologic Agents; Humans; Scleroderma, Localized; Scleroderma, Systemic; Skin; Treatment Outcome; Tretinoin

Topics: Administration, Topical; Adult; Female; Humans; Keratolytic Agents; Middle Aged; Scleroderma, Systemic; Treatment Outcome; Tretinoin

Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored.. High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis.. The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis.. Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.

Topics: Animals; Biomarkers; Fibrosis; Glucuronides; Humans; Lung Diseases, Interstitial; Mice; Scleroderma, Systemic; Tretinoin

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.

Topics: Animals; Bleomycin; Collagen Type I; Disease Models, Animal; Fibroblasts; Fibrosis; Mice; Mice, Transgenic; Receptors, Retinoic Acid; Scleroderma, Systemic; Skin; Transcription Factor AP-1; Tretinoin

Retinoic acid (RA) is an active metabolite of vitamin A and has been reported to improve the clinical symptoms of patients with systemic sclerosis (SSc). However, the mechanism of RA in the prevention of SSc remains unclear. Regulatory T cells (Tregs) are a subpopulation of T cells with immunosuppressive activity. The quantitative and functional defects of Tregs may mediate the immune dysfunction in SSc. The addition of all-trans retinoic acid (ATRA) to human naïve CD4+ cells could promote the maturation of Tregs and increase the stable expression of Foxp3. In this study, we explored the role of RA on Tregs in SSc CD4+ T cells and its possible epigenetic mechanisms, so as to further understand the mechanisms of RA on SSc.. CD4+ T cells were isolated from peripheral blood of SSc and treated with or without ATRA and/or transforming growth factor-. The expression of Tregs and FOXP3 in CD4+ T cells from patients with SSc increased in response to ATRA. Moreover, combined stimulation with ATRA and TGF-. ATRA acts as an inducer of Treg response in SSc CD4+ T cells via demethylation of the FOXP3 promoter and activation of FOXP3 expression. This may be one of the molecular mechanisms for ATRA, and therefore, RA can be used for the treatment of SSc.

Topics: CD4 Antigens; Cell Differentiation; Cells, Cultured; Demethylation; DNA Methylation; Epigenesis, Genetic; Flow Cytometry; Forkhead Transcription Factors; Humans; Interleukin-2 Receptor alpha Subunit; Scleroderma, Systemic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin; Up-Regulation

The pathogenesis of systemic sclerosis (SSc) is not fully understood and there is no effective treatment for this disease. Retinoic acid (RA) can modulate connective tissue metabolism, exhibit anti-fibrotic activity, and improve the clinical symptoms of SSc. However, the mechanisms by which RA elicits its anti-fibrotic actions remain to be determined. The aim of this study was to elucidate the underlying mechanisms by which RA exerts beneficial effects on scleroderma. Cultured skin fibroblasts from patients with scleroderma were treated with RA and their effect on the expression of 5-lipoxygenase (LOX), transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF), type I and type III collagen was tested by reverse transcription polymerase chain reaction (RT-PCR) and western immunoblotting. The effect of MK886, a 5-LOX-specific inhibitor, on the expression of TGF-β1, CTGF, type I and type III collagen was also examined by RT-PCR. In cultured scleroderma fibroblasts, the expression of 5-LOX was elevated compared with normal human dermal fibroblasts. RA significantly inhibited the expression of 5-LOX and of TGF-β1, CTGF, type I and type III collagen. We further found that the expression of TGF-β1, CTGF and type I and type III collagen mRNA was inhibited by MK886 in scleroderma fibroblasts. In vitro, RA reduced 5-LOX expression in scleroderma fibroblasts and downregulated TGF-β1 and CTGF expression, leading to the inhibition of type I and type III collagen synthesis. Our results indicate that the clinical effects of RA on scleroderma are, at least in part, attributable to the reduction of 5-LOX expression and the subsequent suppression of TGF-β1 and CTGF expression that results in the blockade of collagenogenesis.

Topics: Adult; Aged; Arachidonate 5-Lipoxygenase; Cells, Cultured; Collagen; Connective Tissue Growth Factor; Female; Fibroblasts; Gene Expression; Humans; Indoles; Lipoxygenase Inhibitors; Male; Middle Aged; Scleroderma, Systemic; Skin; Transforming Growth Factor beta1; Tretinoin

The pathogenesis of scleroderma (SSc) is not fully understood, and there is no effective treatment for this chronic disease. Retinoic acid (RA) can modulate connective tissue metabolism, exhibit antifibrotic activity and improve the clinical symptoms of patients with SSc. However, the mechanisms by which RA elicits its antifibrotic actions remain to be determined.. To elucidate the underlying mechanisms by which retinoids exert beneficial effects on SSc.. Cultured skin fibroblasts from patients with SSc were treated with retinoids (9-cis-, 13-cis- and all-trans-retinoic acid) and their effect on the expression of cyclooxygenase (COX)-2, connective tissue growth factor (CTGF) and type I and III collagen and on the production of PGE(2) was examined. COX-2 expression was analysed by western immunoblotting, PGE(2) production by enzyme immunoassay and CTGF expression, and type I and III collagen expression by reverse transcriptase PCR and western immunoblotting.. In cultured SSc fibroblasts, 9-cis-RA significantly increased COX-2 protein expression and PGE(2) production and inhibited the expression of CTGF and type I and III collagen. We further found that expression of CTGF and of type I and III collagen mRNA was inhibited by exogenous PGE(2) in SSc fibroblasts.. In vitro, 9-cis-RA induced COX-2 expression and PGE(2) production in SSc fibroblasts and PGE(2) downregulated CTGF expression, leading to the inhibition of type I and III collagen synthesis. Our results indicate that the clinical effects of 9-cis-RA on SSc are, at least in part, attributable to the induction of PGE(2) and the subsequent suppression of CTGF expression that results in the blockade of collagenogenesis.

Topics: Adult; Aged; Alitretinoin; Collagen Type I; Collagen Type II; Connective Tissue Growth Factor; Cyclooxygenase 2; Dinoprostone; Enzyme Induction; Female; Fibroblasts; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Middle Aged; Scleroderma, Systemic; Tretinoin

Four patients with systemic scleroderma (SSc), 4 patients with morphea, and 4 patients with hypertrophic scar were treated with topical tocoretinate for 6 months to 3 years and studied clinically and histopathologically. Clinically, all of the lesions responded to this therapy. The stiffness of the skin lesions, glossy appearance of the lesions, and telangiectasia improved. Histopathologically, the proliferated collagen fibers decreased in thickness, and the inter-fiber spaces increased. Immunoreactive tenascin-C expressed in the proliferated deep dermal fibers of the SSc and hypertrophic scar lesions was markedly decreased compared with the level before the topical tocoretinate therapy. Topical tocoretinate has been used for the treatment of ulcers; it is also a potent treatment for sclerotic skin diseases.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Child, Preschool; Cicatrix, Hypertrophic; Drug Combinations; Female; Humans; Middle Aged; Scleroderma, Localized; Scleroderma, Systemic; Skin; Tretinoin; Vitamin E

Epidermal growth factor receptor (EGF-R) of fibroblasts from 3 patients with scleroderma (progressive systemic sclerosis, PSS) was studied by radioiodinated-EGF binding assay. The binding was 60.9 +/- 4.0% of normal fibroblasts, and the Scatchard plots showed a decrease in the affinity for EGF, not in the number of EGF-R. PSS fibroblasts expressed higher levels (1.15-2.45-fold) of RNA for the v-erbB (EGF-R gene). All-transretinoic acid (retinoid) had little effect on EGF-R, v-erbB gene expression and the proliferation of PSS fibroblasts. These data concerning the abnormality in the EGF-R may all constitute a feature of PSS fibroblasts.

Topics: Cell Division; Epidermal Growth Factor; ErbB Receptors; Female; Fibroblasts; Gene Expression Regulation; Humans; Middle Aged; Oncogenes; Reference Values; Scleroderma, Systemic; Statistics as Topic; Stimulation, Chemical; Time Factors; Tretinoin

In the present study, we have determined the specific glucocorticoid receptors in cultured human skin fibroblasts with [3H]dexamethasone as the ligand. The whole-cell assay was employed for determination of glucocorticoid receptor densities and binding affinities in fibroblast cultures established either from 16 healthy control subjects, from 4 patients with active progressive systemic sclerosis (PSS), from 3 patients with keloids and 3 patients with diabetes mellitus. The receptor densities in PSS, keloid, diabetes and control fibroblasts were in the same range, the values being 6.3 +/- 4.9, 7.7 +/- 3.6, 5.3 +/- 1.3 and 7.9 +/- 6.2 fmol/micrograms DNA (mean +/- SD), respectively. In further studies, the cells were incubated with 10(-7) M dexamethasone for 4 or 9 days before the receptors were assayed. The specific binding of [3H]dexamethasone in steroid treated cultures was 62 and 13% of that observed in controls, suggesting down-regulation. In contrast, incubation of fibroblasts with 10(-5) M all-trans-retinoic acid did not alter the binding of [3H]dexamethasone, suggesting lack of pharmacologic interference at the receptor level.

Topics: Cells, Cultured; Dexamethasone; Diabetes Mellitus; Fibroblasts; Humans; In Vitro Techniques; Keloid; Receptors, Glucocorticoid; Scleroderma, Systemic; Skin; Tretinoin

Topics: Female; Humans; Isomerism; Isotretinoin; Scleroderma, Systemic; Tretinoin