Cathepsin-L, a Key Molecule in the Pathogenesis of Drug-Induced and I-Cell Disease-Mediated Gingival Overgrowth

Abstract

Drug-induced gingival overgrowth, the chronic side effect of calcium antagonists, is frequently seen due to the increase in patients with hypertension, although the etiology of the disease is largely unknown. I-cell disease, which accompanies gingival overgrowth, is characterized by a deficiency in UDP-N-acetyl-glucosamine and is classified as one of the lysosomal storage diseases. Here, we hypothesized that a common mechanism may underlie the etiology of gingival overgrowth seen in patients treated with calcium antagonist and in patients with I-cell disease. A calcium antagonist, nifedipine, specifically suppressed cathepsin-L activity and mRNA expression, but not that of cathepsin-B in cultured gingival fibroblasts. The activity of cathepsin-L was suppressed up to 50% at 24 hours after treatment of the cells with the reagent. The selective suppression of cathepsin-L activity appeared not to be dependent on Ca(2+), since treatment of the cells with thapsigargin suppressed both cathepsin-B and -L activity. Mice deficient in the cathepsin-L gene manifested enlarged gingivae. Histological observation of the gingivae demonstrated typical features of acanthosis, a phenotype very similar to that of experimentally induced gingival overgrowth. Since cathepsin-L deficiency was reported to be associated with thickening of the skin, impaired cathepsin-L activity may play a key role in the establishment of skin and gingival abnormalities seen in I-cell disease. In addition, reduced cathepsin-L activity may play an important role in inducing drug-induced gingival overgrowth.

cAMP-response element binding protein (CREB) regulates cyclosporine-A-mediated down-regulation of cathepsin B and L synthesis

“…In addition, we have demonstrated that longterm exposure to CsA impairs both cathepsin B and L activity in HGFs (Yamaguchi et al 2004). Importantly, we have observed that mice deficient in the cathepsin L gene manifest enlarged gingiva (Nishimura et al 2002). These observations support the notion that the down-regulation of cathepsin B or L plays an crucial role in the development of gingival overgrowth.…”

Connective Tissue Metabolism and Gingival Overgrowth

“…Consistent results were found in cathepsin-L-deficient mice that exhibited enlarged gingival epithelial and connective tissues (Nishimura et al, 2002). The authors note that humans lacking lysozomal enzymes as a result of the rare genetic disease I-cell disease or mucolipidosis also have gingival overgrowth (Nishimura et al, 2002). Thus, inhibition of phagocytosis or of lysozomal enzymes appears likely to be a mechanism that could contribute to gingival overgrowth.…”

“…Cyclosporin may also inhibit phagocytosis of type I collagen in vitro and in vivo (Kataoka et al, 2000;Arora et al, 2001). Consistent results were found in cathepsin-L-deficient mice that exhibited enlarged gingival epithelial and connective tissues (Nishimura et al, 2002). The authors note that humans lacking lysozomal enzymes as a result of the rare genetic disease I-cell disease or mucolipidosis also have gingival overgrowth (Nishimura et al, 2002).…”

The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling

“…Major insights into the function of cathepsin L in the skin result from analysis of mice with targeted inactivation of the CTSL gene (ctsl -/-mice) and from the spontaneous mouse mutations nackt (ctsl nkt /ctsl nkt ) and furless (fs -/fs -) for which the cathepsin L gene has been identified as the target (Benavides et al, 2002;Roth et al, 2000). Cathepsin L-deficient (ctsl -/-) mice develop periodic hair loss, gingival acanthosis and epidermal hyperplasia with hyperkeratosis (Nishimura et al, 2002;Tobin et al, 2002). Impaired differentiation of hair follicle epithelial cells and hyperproliferation of basal epidermal keratinocytes are the primary characteristics of the ctsl -/-phenotype.…”