Gene/Protein Disease Symptom Drug Enzyme Compound
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Diabetes induces osteopenia, which is characterized by a deficiency of osteoid and decreased activity of osteoblasts. We recently found that tetracyclines prevent the loss of osteoid and bone matrix and the degeneration of osteoblasts in diabetic rats by a mechanism independent of their antimicrobial efficacy. However, bone remodeling requires the activity of osteoclasts as well as osteoblasts. To determine the in vivo effects of tetracycline on osteoclasts in long bones, either a tetracycline (minocycline, TC) or its chemically modified non-antibiotic analogue (CMT), 4-de-dimethylaminotetracycline, was administrated daily to streptozotocin-induced diabetic rats by oral intubation. After 21 days, the rats were perfusion-fixed with a mixture of formaldehyde and glutaraldehyde, and the humeri were dissected and processed for ultracytochemical demonstration of acid trimetaphosphatase (ACPase) activity. In untreated non-diabetic (control) rats, the osteoclasts at the zone of provisional ossification exhibited abundant mitochondria and cisterns of rough endoplasmic reticulum (RER) throughout the cytoplasm, prominent stacks of Golgi membranes, and lysosomes in the perinuclear cytoplasm, and numerous various pale vacuoles in the cytoplasmic area adjacent to well-developed ruffled border. Intense ACPase activity was observed in the Golgi saccules, lysosomes, pale vacuoles, and the extracellular canals of ruffled border. The reaction products were also noted along the resorbing bone surfaces associated with the osteoclast ruffled border. The osteoclasts in the untreated diabetic rats showed a cytoplasmic organization similar to that of the non-diabetic control rats, but showed little or no ruffled border which was replaced by a broad clear zone in some of these cells. However, most of the osteoclasts on bone matrix in the diabetics were devoid of both a ruffled border and a clear zone. ACPase activity was detected in the osteoclast cytoplasm of diabetic rat, as in the controls, but to a much lesser extent along the broad clear zone facing the resorbing bone surfaces. The osteoclasts in TC-treated diabetic rats possessed both a clear zone and a small ruffled border. However, in some cases, they lacked both structures reminiscent of the untreated diabetic cells. The osteoclasts of CMT-treated diabetic rats exhibited structural and enzymatic features essentially identical to those of the non-diabetic control rats. These results suggest that the diabetes-induced osteopenia results, at least in part, from degeneration of osteoclasts (as well as atrophic osteoblasts) and that tetracyclines may be effective in preventing these abnormalities by a mechanism not dependent on the drugs' antimicrobial properties.
Anat Rec 1990 Aug
PMID:Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts in streptozotocin-induced diabetic rats. 216 33

The enamel organ of growing rat incisors was perfusion-fixed with a mixture of formaldehyde and glutaraldehyde and processed for ultracytochemical demonstration of ouabain-resistant, K+-stimulated p-nitrophenylphosphatase representing the second dephosphorylative step of H-K-ATPase by use of the one-step lead method. Throughout the stages of amelogenesis, the enzymatic activity was found in the plasma membranes, mitochondrial membranes, and lysosomal structures of the cells of stratum intermedium, papillary layer, and ameloblast layer. Gap junctions and desmosomes between these cells were, however, free of reaction product or showed slight precipitates of reaction. The stellate reticulum and the outer enamel epithelium at the stage of enamel secretion were usually negative for reaction. Although secretory, transition, and ruffle-ended maturation ameloblasts showed enzymatic activity at their basolateral cell surfaces, their distal cell surfaces facing the enamel were always free of reaction product. On the other hand, the smooth-ended maturation ameloblasts seldom showed a positive reaction, except in lysosomes and along their basal cell surfaces. An energy-dispersive X-ray microanalysis of reaction products of H-K-ATPase in unosmicated tissue sections demonstrated that they were composed of lead and phosphorus, which had been released during the dephosphorylation of substrate. In cytochemical controls, the enzymatic activity was completely dependent on substrate and potassium ion, resistant to ouabain and levamisole, and inhibited by nolinium bromide, a specific inhibitor of H-K-ATPase. In addition, inorganic trimetaphosphatase as enzymatic marker of lysosome was localized in dark and pale lysosomes, phagosomes, multivesicular bodies, and ferritin-containing vesicles of the ameloblasts and the cells of stratum intermedium and papillary layer. These membrane-bound structures were also positive for H-K-ATPase reaction. These results suggest that: 1) H-K-ATPase functions to maintain an acidic internal pH of lysosomes in the enamel organ cells; and 2) H-K-ATPase localization in the plasma membranes of enamel organ cells is concerned with efflux of protons derived from cytoplasmic water.
Anat Rec 1988 Aug
PMID:H+-K+-ATPase activity in the rat incisor enamel organ during enamel formation. 284 91

To investigate the mechanisms involved in the atrophy of the intestines in lampreys (Lampetra japonica) during the spawning migration stage, we examined by morphological methods their intestines with special reference to degradation of extracellular matrix (ECM) components. Stellate cells are known to be distributed not only in the liver (hepatic stellate cells) but also in other organs, such as the pancreas, intestine, lung, and kidney (extrahepatic stellate cells). Hepatic stellate cells are well known to be able to biosynthesize, secrete, and degrade ECM. Therefore, we investigated the cellular and molecular mechanisms involved in the atrophy of the intestines by focusing on these intestinal extrahepatic stellate cells. The cells were found to contain phagocytosed and degraded collagen fibrils, which are one of the ECM components. A positive reaction for trimetaphosphatase (TMPase, a cytochemical marker of lysosomes) was preferentially detected in round or elongated vesicles in the intestinal extrahepatic stellate cells and the deposits of the reaction products coexisted with the degraded collagen fibrils. However, the basement membrane of the intestine, which membrane is also an ECM component, was preserved throughout the spawning migration stage of the lamprey and accumulated as a mass of thick membrane, suggesting the existence of a special mechanism for selective digestion of ECM components. These results indicate that the intestinal extrahepatic stellate cells in Lampetra japonica during its spawning migration stage might play an important mechanistic role in the atrophy of lamprey intestines by phagocytizing collagen fibrils and digesting the phagocytized collagen fibrils in their lysosomes.
Anat Rec A Discov Mol Cell Evol Biol 2005 Jul
PMID:Degradation of extracellular matrix by extrahepatic stellate cells in the intestine of the lamprey, Lampetra japonica. 1591 28