Matrix metalloproteinases as mediators of tissue injury in different forms of cutaneous lupus erythematosus.
ABSTRACT Matrix metalloproteinases (MMPs) contribute to tissue destruction, regeneration, inflammation and apoptosis and several of them are upregulated by ultraviolet (UV) radiation in skin. Although some MMPs associate with organ manifestations of systemic lupus erythematosus (SLE), their role in cutaneous lupus erythematosus (LE) is elusive.
Our aim was to evaluate the expression of MMPs in SLE, subacute cutaneous LE (SCLE) and discoid LE (DLE) skin lesions and their relation to apoptosis and epidermal changes.
Lesional skin biopsies from 20 patients with SLE, 20 with DLE and 17 with SCLE, and from UVA/UVB-photoprovoked skin of healthy volunteers were immunostained using antibodies to multiple MMPs and tissue inhibitors of metalloproteinases (TIMPs). The TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling) method was used for detection of apoptosis.
MMP-3, -10, -19 and -26 were abundantly expressed by keratinocytes in SLE, DLE and SCLE skin samples. MMP-7 was detected in keratinocytes in regions of oedema and vacuolization especially in SLE and SCLE, while MMP-14 was only occasionally observed in keratinocytes. Photoprovocation did not induce MMP-10 or -26 expression in skin of healthy volunteers. Epithelial TIMP-1 expression was low while occasional positive fibroblasts were seen in the dermis. TIMP-3 was abundantly expressed in the epidermis, endothelial cells and macrophages.
Different subtypes of cutaneous LE are fairly similar in their MMP expression profile. MMP-3 and -10 mediate both epidermal changes and dermal tissue remodelling but are not present in lymphocytes. Low expression of TIMP-1 suggests that lupus skin is characterized by proteolytic events, and targeted action using selective MMP inhibitors may reduce lupus-induced damage in inflamed tissues.
- SourceAvailable from: Abdul Rahman Al-Azri[Show abstract] [Hide abstract]
ABSTRACT: Matrix metalloproteinases (MMPs) are critical factors in maintaining the integrity of mucosa and mediating normal biological processes. An imbalance between tissue levels of these mediators and their natural inhibitors is believed to underlie the pathophysiology of many diseases, including those affect the gastrointestinal and oral mucosae. The ongoing development of synthetic inhibitors of these mediators may provide opportunities to develop treatment modalities for patients suffering from these diseases. Understanding the role of MMPs in the pathophysiology of many diseases, however, is far from complete, and the improvement of pharmaceutical management strategies can only be achieved if the underlying process of these diseases is completely comprehended. This paper reviews the functions of matrix metalloproteinases and addresses their role in mediating mucosal pathologies with emphasis on oral mucosa.Oral Diseases 09/2012; · 2.40 Impact Factor
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ABSTRACT: The role of metalloproteinase-10 (MMP-10) in type 1 diabetes is not known. We hypothesise that it plays a role in the onset and progression of diabetic nephropathy and retinopathy. Serum MMP-10 levels from 269 patients with type 1 diabetes were measured, and their association with microvascular complications was analysed. We also studied whether knocking out the Mmp10 gene influenced the extent of renal injury and retinal damage in a streptozotocin-induced diabetic mouse model. The risk of nephropathy and proliferative retinopathy associated with the highest vs the lowest MMP-10 tertile was increased three to four times independently of the classical risk factors. Accordingly, renal function and morphology were better preserved in diabetic Mmp10 (-⁄-) mice than in their Mmp10 (+/+) counterparts. There were more kidney-infiltrating macrophages in diabetic Mmp10(+/+) mice, suggesting that MMP-10 contributes to the inflammatory response leading to microvascular complications. The loss of neuronal cells in the retinas of diabetic Mmp10 (+/+) mice was higher than in Mmp10 (-⁄-) mice. Retinal inflammation was decreased in Mmp10 (-⁄-) mice, as indicated by their reduced retinal caspase-1 levels. MMP-10 is involved in the development of microvascular complications in type 1 diabetes and emerges as a potential therapeutic target for slowing down the evolution of diabetic nephropathy and retinopathy.Diabetologia 09/2013; · 6.88 Impact Factor
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ABSTRACT: Patients with systemic lupus erythematosus (SLE) have a high prevalence of abnormal bone metabolism and vitamin D deficiency. Genetic studies have provided the opportunity to determine the specific proteins linking vitamin D to SLE pathology [i.e., major histocompatibility complex (MHC) class II molecules, the vitamin D receptor (VDR), microRNAs (miRNAs), the renin-angiotensin system (RAS), apolipoprotein E (ApoE), liver X receptor (LXR), and toll-like receptors (TLRs)]. Vitamin D also exerts protective effects against SLE through non-genomic factors, such as ultraviolet radiation (UV) exposure, matrix metalloproteinase (MMPs), heme oxygenase-1 (HO-1), the prostaglandins (PGs), cyclooxygenase-2 (COX-2), and oxidative stress. Thus, vitamin D may play a beneficial role in SLE. Moreover, the use of calcitriol or 1α,25-dihydroxyvitamin D(3) is optimal for the treatment of SLE patients because this active form of the vitamin D(3) metabolite can modulate inflammatory cytokine production. However, further investigation into the effects of calcitriol with SLE is warranted.Clinical Rheumatology 07/2012; 31(10):1423-35. · 1.77 Impact Factor