Editorial. Oral submucous fibrosis: revised hypotheses as to its cause.

Oral submucous fbrosis (OSF), being a prototype of pathological fbrosis, remains enigmatic as regards its causation. The connective tissue production is permanent and there is no reversal of the condition even after cessation of the habit of areca-nut usage; prime suspect in its causation.(1) The bulk of the connective tissue consists of type-1 collagen(2) and its formation does not appears to be caused by excessive proliferation of fbroblasts.(3) The effect of areca nut extract on in vitro fbroblasts varies on a concentration gradient, predominantly suppressing rather than stimulating the growth of the cells.(4) Based on morphological characteristics, the fbroblast population in the diseased mucosa has been classifed in to types F1, F2 and F3 with F3 cells producing signifcantly more collagen than the other two cell types. It was concluded that a change of fbroblast population has occurred in OSF and that this relative increase of F3 cells in humans, could be committed to the production of large quantities of collagen formation in OSF. It has been proposed that fbroblasts are functionally heterogeneous, the composition of any given normal or diseased connective tissue being a consequence in part of its particular mixture of fbroblast subtypes and density. Subtype deletion or amplifcation can result from selective cytotoxic or mitogenic responses induced by the binding environmental ligands.(5) Against this backdrop, we propose few de-novo attributes, hitherto unreported, and seem to be of relevance in the pathogenesis of OSF; namely the role of autophagy in basic cellular homeostatic process, important to cell fate decisions under conditions of stress and also ECM producing cells (fbroblasts, myofbroblasts and smooth muscle cells) derived from epithelial and endothelial cells through process termed epithelial and endothelial-mesenchymal transition.

Visualization of mitochondria with green fluorescent protein in cultured fibroblasts from patients with mitochondrial diseases.

cDNAs for green fluorescent protein (GFP) and for a GFP fusion protein containing the presequence of human ornithine transcarbamylase (pOTC-GFP) were transfected into cultured human fibroblasts. GFP cDNA gave diffuse fluorescence throughout the cytoplasm and the nucleus, whereas pOTC-GFP cDNA gave mitochondria-associated fluorescence. Fluorescent mitochondrial structures could be classified into five patterns: thread-like mitochondria, fine thread-like ones, rod-like ones, granular ones, and granular ones with weak cytosolic fluorescence. pOTC-GFP mutants resulted in a loss of mitochondrial fluorescence and an appearance of weak fluorescence throughout the cytoplasm. pOTC-GFP cDNA was transfected into fibroblasts from patients with various mitochondrial diseases. Higher ratios of fibroblasts with granular mitochondria and those with fine thread-like ones were observed in a patient with Reye's syndrome and a patient with Kearns-Sayre syndrome. Weak cytosolic fluorescence was sometimes observed in fibroblasts from these patients. This method will be useful to analyze mitochondrial structural alterations and disorders of mitochondrial protein import.

Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats. Studies on secretion by synovial fibroblast-like cells and immunohistologic localization.

The growth of synovial fibroblast-like cells from patients with rheumatoid arthritis and rats with streptococcal cell wall (SCW)-induced arthritis in vitro under anchorage-independent conditions is inhibited by transforming growth factor-beta (TGF-beta). Because this growth factor is present in rheumatoid synovial fluids, we studied whether this cytokine might be secreted by cells in rheumatoid synovial tissue. We show that synovial tissues from patients with rheumatoid arthritis and osteoarthritis, and rats with SCW-induced arthritis, contain TGF-beta-1 mRNA. TGF-beta, predominantly type 1, was spontaneously secreted in vitro by synovial tissue explants and synovial fibroblast-like cells. In addition, TGF-beta could be detected immunohistochemically in cells throughout rheumatoid and SCW-induced arthritic rat synovial tissues. Finally, exogenous TGF-beta induced collagen and inhibited collagenase mRNA levels by cultured synoviocytes. These data support an autocrine role for TGF-beta in the regulation of synoviocytes in rheumatoid arthritis and, in light of its demonstrated effects on the immune system, suggest that TGF-beta might also have important paracrine effects on infiltrating inflammatory cells.