metallothionein and Arthritis

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Arthritis; Asthma; Cytokines; Extracellular Matrix; Fever; Heat-Shock Proteins; Humans; Inflammation; Leukotrienes; Metallothionein; Phagocytosis; Platelet Activating Factor; Prostaglandins

Metallothioneins (MTs) are low-molecular-weight cytosolic proteins, which are thought to participate in metal homeostasis and protection against metal toxicity and oxidative stress. MT synthesis can be induced by a variety of inflammatory mediators and antirheumatic drugs, and high levels of MT have been implicated in resistance of cells to some antirheumatic drugs. We studied the expression and localization of MT in synovial tissue samples from patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or osteoarthritis (OA) by quantitative immunohistochemistry. Immunostaining for MT was detected in a large number of intimal lining cells in most of the investigated synovial tissue samples (75%). In a smaller proportion of samples (42%), some of the fibroblast-like cells of the subsynovial layer were also MT positive. Immunostaining and double-staining experiments with antibodies against monocyte-, macrophage- and leucocyte-associated antigens suggested that most of the MT-positive cells were intimal fibroblast-like cells and subsynovial fibroblasts. However, there were no statistically significant differences in the intensity of staining for MT between the rheumatic diseases and OA at the single-cell level. Thus, MT is expressed in synovial tissue and may participate in homeostatic and protective functions. The interindividual variability in the expression of MT in synovial tissue may be related to the therapeutic efficacy of the gold compounds and chemotherapeutic antirheumatic drugs sequestered by MT.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Arthritis; Arthritis, Psoriatic; Arthritis, Rheumatoid; Child; Female; Humans; Immunohistochemistry; Joint Diseases; Male; Membrane Glycoproteins; Metallothionein; Mice; Middle Aged; Muramidase; Osteoarthritis; Spondylitis, Ankylosing; Synovial Membrane

D-penicillamine does not remove copper from metallothionein, but it has been suggested that it may increase hepatic metallothionein levels. D-penicillamine was shown to increase rat hepatic metallothionein levels; however, the effect was dependent on an interaction with copper. The drug accelerated the excretion of exogenous copper but increased the amount retained on metallothionein. This interaction of penicillamine and copper also provoked changes in the distribution of zinc and in particular an increase in the heat-stable cytosol zinc fraction. In contrast, thiomolybdates were much more effective in eliminating exogenous copper and even removed copper that was already bound to metallothionein; thus, the copper level in the heat-stable cytosol fraction decreased. The observations support the view that patients with Wilson's disease may not be truly "decoppered" but that treatment with d-penicillamine is effective because the accumulated copper in the liver is bound in a nontoxic form by the increased metallothionein. The results explain why cessation of treatment is dangerous. The results may also partially explain the effectiveness of D-penicillamine copper chelates as antiinflammatory drugs.

Topics: Animals; Arthritis; Copper; Cytosol; Hepatolenticular Degeneration; Humans; Injections, Intramuscular; Liver; Male; Metallothionein; Methionine; Molybdenum; Organometallic Compounds; Penicillamine; Rats; Rats, Inbred Strains; Reference Values; Zinc

The induction of ceruloplasmin and metallothionein was investigated in rats with the early inflammatory phase of adjuvant arthritis. When examined at the peak of the acute inflammatory response, 5 days after adjuvant treatment, zinc given daily (2 mg/kg, intraperitoneally) increased serum ceruloplasmin levels by 2.0 times that found in nonarthritic rats and 1.2 times that found in non-zinc-treated arthritic rats. 13-cis-Retinoic acid (160 mg/kg, orally) given daily increased serum ceruloplasmin 2.2 and 2.7 times that found in nontreated arthritic rats when given alone and with zinc (2 mg/kg, intraperitoneally), respectively. Reduction in the inflammatory response was measured by weight of the adjuvant-injected paw, 5 days after adjuvant was administered. The reduction in inflammation was 13 and 19-20% for 13-cis-retinoic acid and zinc, respectively, when given alone, and between 26 and 31% when the treatments were combined. Zinc markedly increased liver metallothionein levels whereas 13-cis-retinoic acid was a much less potent inducer of the protein in liver. The results are discussed in light of the probable physiological roles of both ceruloplasmin and metallothionein.

Topics: Animals; Arthritis; Arthritis, Experimental; Ceruloplasmin; Isotretinoin; Male; Metallothionein; Rats; Rats, Inbred Strains; Tretinoin; Zinc